3-alkyl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors

ABSTRACT

The present disclosure relates to inhibitors of zinc-dependent histone deacetylases (HDACs) useful in the treatment of diseases or disorders associated with an HDAC, e.g., HDAC6, having a Formula I: 
                         
where R, L, X 1 , X 2 , X 3 , X 4 , Y 1 , Y 2 , Y 3 , and Y 4  are described herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. Non-Provisional applicationSer. No. 15/013,820, filed Feb. 2, 2016, which claims the benefit ofpriority of U.S. Provisional Application No. 62/110,716, filed Feb. 2,2015 and U.S. Provisional Application No. 62/205,438, filed Aug. 14,2015, each of which is incorporated herein by reference.

FIELD OF THE INVENTION

The present disclosure relates to inhibitors of zinc-dependent histonedeacetylases (HDACs) useful in the treatment of diseases or disordersassociated with HDACs including cell proliferation diseases (e.g.,cancer), neurological and inflammatory diseases. Specifically, thisdisclosure is concerned with compounds and compositions inhibitingHDACs, methods of treating diseases associated with HDACs, and methodsof synthesizing these compounds.

BACKGROUND OF THE INVENTION

Many members of the HDAC family require zinc (Zn) to function properly.For instance, the isozyme histone deacetylase 6 (HDAC6) is azinc-dependent histone deacetylase that possesses histone deacetylaseactivity. Other family members include HDACs 1-5 and 7-11. (De Ruijteret al, Biochem. J. 2003. 370; 737-749).

HDAC6 is known to deacetylate and associate with α-tubulin, cortactin,heat shock protein 90, ß-catenin, glucose-regulated protein 78 kDa,myosin heavy chain 9, heat shock cognate protein 70, and dnaJ homologsubfamily A member 1 (reviewed in Li et al, FEBS J. 2013, 280: 775-93;Zhang et al, Protein Cell. 2015, 6(1): 42-54). Diseases in which HDAC6inhibition could have a potential benefit include cancer (reviewed inAldana-Masangkay et al, J. Biomed. Biotechnol. 2011, 875824),specifically: multiple myeloma (Hideshima et al, Proc. Natl. Acad. Sci.USA 2005, 102(24):8567-8572); lung cancer (Kamemura et al, Biochem.Biophys. Res. Commun. 2008, 374(1):84-89); ovarian cancer (Bazzaro etal, Clin. Cancer Res. 2008, 14(22):7340-7347); breast cancer (Lee et al,Cancer Res. 2008, 68(18):7561-7569; Park et al, Oncol. Rep. 2011, 25:1677-81; Rey et al, Eur. J. Cell Biol. 2011, 90: 128-35); prostatecancer (Seidel et al, Biochem. Pharmacol. 2015 (15)00714-5); pancreaticcancer (Nawrocki et al, Cancer Res. 2006, 66(7):3773-3781); renal cancer(Cha et al, Clin. Cancer Res. 2009, 15(3): 840-850); hepatocellularcancer (Ding et al, FEBS Lett. 2013, 587:880-6; Kanno et al, Oncol. Rep.2012, 28: 867-73); lymphomas (Ding et al, Cancer Celllnt. 2014, 14:139;Amengual et al, Clin Cancer Res. 2015, 21(20):4663-75); and leukemiassuch as acute myeloid leukemia (AML) (Fiskus et al, Blood 2008,112(7):2896-2905) and acute lymphoblastic leukemia (ALL)(Rodriguez-Gonzalez et al, Blood 2008, 112(11): Abstract 1923)).

Inhibition of HDAC6 may also have a role in cardiovascular disease,including pressure overload, chronic ischemia, andinfarction-reperfusion injury (Tannous et al, Circulation 2008,117(24):3070-3078); bacterial infection, including those caused byuropathogenic Escherichia coli (Dhakal and Mulve, J. Biol. Chem. 2008,284(1):446-454); neurological diseases caused by accumulation ofintracellular protein aggregates such as Alzheimer's, Parkinson's andHuntington's disease (reviewed in Simoes-Pires et al, Mol. Neurodegener.2013, 8: 7) or central nervous system trauma caused by tissue injury,oxidative-stress induced neuronal or axomal degeneration (Rivieccio etal, Proc. Natl. Acad. Sci. USA 2009, 106(46):19599-195604); andinflammation and autoimmune diseases through enhanced T cell-mediatedimmune tolerance at least in part through effects on regulatory T cells,including rheumatoid arthritis, psoriasis, spondylitis arthritis,psoriatic arthritis, multiple sclerosis, lupus, colitis and graft versushost disease (reviewed in Wang et al, Nat. Rev. Drug Disc. 20098(12):969-981; Vishwakarma et al, Int Immunopharmacol. 2013, 16:72-8;Kalin et al, J. Med. Chem. 2012, 55:639-51); and fibrotic disease,including kidney fibrosis (Choi et al, Vascul. Pharmacol. 201572:130-140).

Four HDAC inhibitors are currently approved for the treatment of somecancers. These are suberanilohydroxamic acid (Vorinostat; Zolinza®) forthe treatment of cutaneous T cell lymphoma and multiple myeloma;Romidepsin (FK228; FR901228; Istodax®) for the treatment of peripheral Tcell lymphoma; Panobinostat (LBH-589; Farydak®) for the treatment ofmultiple myeloma; and belinostat (PXD101; Beleodaq®) for the treatmentof peripheral T cell lymphoma. However, these drugs are of limitedeffectiveness and can give rise to unwanted side effects. Thus there isa need for drugs with an improved safety-efficacy profile.

Given the complex function of HDAC6 and their potential utility in thetreatment of proliferative diseases, neurological diseases, andinflammatory diseases, there is a need for HDAC inhibitors (e.g., HDAC6inhibitors) with good therapeutic properties.

SUMMARY OF THE INVENTION

One aspect of the disclosure relates to compounds of Formula I:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,tautomers and isomers thereof, wherein:

X¹ is independently CR¹R², NR³, O, or C═O;

X² and X⁴ are each independently CR¹R², C═O, S(O) or SO₂;

X³ is CR^(1′)R^(2′); wherein X⁴, X², and X¹ are not all simultaneouslyCR¹R²;

Y¹ and Y⁴ are not bonded to —C(O)NHOH and are each independently N orCR¹;

Y² and Y³ are each independently N or CR¹ when not bonded to —C(O)NHOHand Y² and Y³ are C when bonded to —C(O)NHOH;

L is a bond, —(CR¹R²)_(n)—, —C(O)O—, —C(O)NR³—, —S(O)₂—, —S(O)₂NR³—,—S(O)—, or —S(O)NR³—, wherein L is bound to the ring nitrogen throughthe carbonyl or sulfonyl group;

R is independently —H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₄-C₈cycloalkenyl, —C₂-C₆ alkynyl, —C₃-C₈ cycloalkyl, —C₅-C₁₂ spirocycle,heterocyclyl, spiroheterocyclyl, aryl, or heteroaryl containing 1-5heteroatoms selected from the group consisting of N, S, P, and O,wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl,spirocycle, heterocyclyl, spiroheterocyclyl, aryl, or heteroaryl isoptionally substituted with one or more —OH, halogen, oxo, —NO₂, —CN,—R¹, —R², —OR³, —NHR³, —NR³R⁴, —S(O)₂NR³R⁴, —S(O)₂R¹, —C(O)R¹, or—CO₂R¹, —NR³S(O)₂R¹, —S(O)R¹, —S(O)NR³R⁴, —NR³S(O)R¹, heterocycle, aryl,or heteroaryl containing 1-5 heteroatoms selected from the groupconsisting of N, S, P, and O;

each R¹ and R² are independently, and at each occurrence, —H, —R³, —R⁴,—C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₄-C₈ cycloalkenyl, —C₂-C₆ alkynyl,—C₃-C₈ cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5heteroatoms selected from the group consisting of N, S, P, and O, —OH,halogen, —NO₂, —CN, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂R⁵, —S(O)₂(C₁-C₆ alkyl), —(C₁-C₆alkyl)S(O)₂R⁵, —C(O)C₁-C₆ alkyl, —CO₂C₁-C₆ alkyl, —N(C₁-C₆alkyl)S(O)₂C₁-C₆ alkyl, or —(CHR⁵)_(n)NR³R⁴, wherein each alkyl,alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, orheteroaryl is optionally substituted with one or more substituentsselected from —OH, halogen, —NO₂, oxo, —CN, —R⁵, —OR³, —NHR³, NR³R⁴,—S(O)₂N(R³)₂—, —S(O)₂R⁵, —C(O)R⁵, —CO₂R⁵, —NR³S(O)₂R⁵, —S(O)R⁵,—S(O)NR³R⁴, —NR³S(O)R⁵, heterocycle, aryl, or heteroaryl containing 1-5heteroatoms selected from the group consisting of N, S, P, and O;

or R¹ and R² can combine with the carbon atom to which they are bothattached to form a spirocycle, spiroheterocycle, or a spirocycloalkenyl;

or R¹ and R², when on adjacent atoms, can combine to form a heterocycle,cycloalkyl, aryl, heteroaryl containing 1-5 heteroatoms selected fromthe group consisting of N, S, P, and O, or cycloalkenyl;

or R¹ and R², when on non-adjacent atoms, can combine to form a bridgingcycloalkyl or heterocycloalkyl;

R^(1′) and R^(2′) are independently, and at each occurrence, —H, —C₁-C₆alkyl, —C₂-C₆ alkenyl, —C₄-C₈ cycloalkenyl, —C₂-C₆ alkynyl, —C₃-C₈cycloalkyl, heterocyclyl, —OH, halogen, —NO₂, —CN, —NHC₁-C₆ alkyl,—N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)₂R⁵,—S(O)₂(C₁-C₆ alkyl), —(C₁-C₆ alkyl)S(O)₂R⁵, —C(O)C₁-C₆ alkyl, —CO₂C₁-C₆alkyl, —N(C₁-C₆ alkyl)S(O)₂C₁-C₆ alkyl, or (CHR⁵)_(n)NR³R⁴, wherein eachalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocyclyl isoptionally substituted with one or more substituents selected from —OH,halogen, —NO₂, oxo, —CN, —R⁵, —OR³, —NHR³, NR³R⁴, —S(O)₂N(R³)₂—,—S(O)₂R⁵, —C(O)R⁵, —CO₂R⁵, —NR³S(O)₂R⁵, —S(O)R⁵, —S(O)NR³R⁴, —NR³S(O)R⁵,heterocycle, aryl, or heteroaryl containing 1-5 heteroatoms selectedfrom the group consisting of N, S, P, and O;

or R^(1′) and R^(2′) can combine with the carbon atom to which they areboth attached to form a spirocycle, spiroheterocycle, or aspirocycloalkenyl;

or R^(1′) and R^(2′) can combine with R¹ or R² on adjacent atoms to forma heterocycle, cycloalkyl, aryl, heteroaryl containing 1-5 heteroatomsselected from the group consisting of N, S, P, and O, or cycloalkenyl;

or R^(1′) and R^(2′) can combine with R¹ or R² on non-adjacent atoms, toform a bridging cycloalkyl or heterocycloalkyl;

R³ and R⁴ are independently, at each occurrence, —H, —C₁-C₆ alkyl,—C₂-C₆ alkenyl, —C₄-C₈ cycloalkenyl, —C₂-C₆ alkynyl, —C₃-C₈ cycloalkyl,heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected fromthe group consisting of N, S, P, and O, —S(O)₂N(C₁-C₆ alkyl)₂,—S(O)₂(C₁-C₆ alkyl), —(C₁-C₆ alkyl)S(O)₂R⁵, —C(O)C₁-C₆ alkyl, —CO₂C₁-C₆alkyl, or —(CHR⁵)_(n)N(C₁-C₆ alkyl)₂, wherein each alkyl, alkenyl,cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl isoptionally substituted with one or more substituents selected from —OH,halogen, —NO₂, Oxo, —CN, —R⁵, —O(C₁-C₆ alkyl), —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —S(O)₂NH(C₁-C₆ alkyl),—C(O)C₁-C₆ alkyl, —CO₂C₁-C₆ alkyl, —N(C₁-C₆ alkyl)S(O)₂C₁-C₆ alkyl,—S(O)R⁵, —S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆ alkyl)S(O)R⁵, heterocycle, aryl,or heteroaryl containing 1-5 heteroatoms selected from the groupconsisting of N, S, P, and O;

or R³ and R can combine with the nitrogen atom to which they areattached to form a heterocycle, wherein each heterocycle or heteroarylis optionally substituted by —R¹, —R², —R⁴, —OR⁴, or —NR⁴R⁵;

R⁵ is independently, and at each occurrence, —H, —C₁-C₆ alkyl, —C₂-C₆alkenyl, —C₄-C₈ cycloalkenyl, —C₂-C₆ alkynyl, —C₃-C₈ cycloalkyl,heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected fromthe group consisting of N, S, P, and O, —OH, halogen, —NO₂, —CN,—NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂N(C₁-C₆alkyl)₂, —S(O)₂C₁-C₆ alkyl, —C(O)C₁-C₆ alkyl, —CO₂C₁-C₆ alkyl, —N(C₁-C₆alkyl)SO₂C₁-C₆ alkyl, —S(O)(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)(C₁-C₆ alkyl) or —(CH₂)_(n)N(C₁-C₆ alkyl)₂; and

n is independently, and at each occurrence, an integer from 0 to 6 and;

provided that when X² and X⁴ are both C═O, X¹ is not NR³.

Another aspect of the disclosure relates to a method of treating adisease or disorder associated with HDAC, e.g., HDAC6 modulation in asubject in need thereof, comprising administering to the subject aneffective amount of a compound of Formula I.

Another aspect of the disclosure is directed to a method of inhibitingan HDAC, e.g., HDAC6. The method involves administering to a patient inneed thereof an effective amount of a compound of Formula I.

Another aspect of the disclosure relates to a compound of Formula I, ora pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer,or isomer thereof, for use in treating or preventing a diseaseassociated with HDAC6 modulation.

Another aspect of the disclosure relates to the use of a compound ofFormula I, or a pharmaceutically acceptable salt, prodrug, solvate,hydrate, tautomer, or isomer thereof, in the manufacture of a medicamentfor treating or preventing a disease associated with HDAC6 modulation.

Another aspect of the disclosure is directed to pharmaceuticalcompositions comprising a compound of Formula I and a pharmaceuticallyacceptable carrier. The pharmaceutically acceptable carrier can furtherinclude an excipient, diluent, or surfactant. The pharmaceuticalcomposition can be effective for treating a disease or disorderassociated with HDAC, e.g., HDAC6, modulation in a subject in needthereof. The pharmaceutical compositions can comprise the compounds ofthe present disclosure for use in treating diseases described herein.The compositions can contain at least one compound of the disclosure anda pharmaceutically acceptable carrier. The disclosure also provides theuse of the compounds described herein in the manufacture of a medicamentfor the treatment of a disease associated with HDACs.

The present disclosure also provides methods for the treatment of humandiseases or disorders including, without limitation, oncological,neurological, inflammatory, autoimmune, infectious, metabolic,hematologic, or cardiovascular diseases or disorders.

The present disclosure also provides compounds that are useful ininhibiting of zinc-dependent HDAC enzymes, for instance HDAC6. Thesecompounds can also be useful in the treatment of diseases includingcancer.

The present disclosure further provides compounds that can inhibit anHDAC, e.g., HDAC6. In some embodiments, the efficacy-safety profile ofthe compounds of the current disclosure can be improved relative toother known HDAC (e.g. HDAC6) inhibitors. Additionally, the presenttechnology also has the advantage of being able to be used for a numberof different types of diseases, including cancer and non-cancerindications. Additional features and advantages of the presenttechnology will be apparent to one of skill in the art upon reading theDetailed Description of the Disclosure, below.

DETAILED DESCRIPTION OF THE INVENTION

HDAC6 is a zinc-dependent histone deacetylase that has two catalyticdomains. HDAC6 can interact with and deacetylate non-histone proteins,including HSP90 and α-tubulin. Acetylation of HSP90 is associated withloss of function of HSP90. HDAC6 is also implicated in the degradationof misfolded proteins as part of the aggresome. Accordingly, inhibitionof HDAC6 can have downstream effects that can play a role in thedevelopment of certain diseases such as cancer. The present disclosureprovides inhibitors of HDACs, e.g., HDAC6 and methods for using the sameto treat disease.

In a first aspect of the disclosure, compounds of the Formula I aredescribed:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,tautomers, and isomers thereof, wherein R, L, X¹, X², X³, X⁴, Y¹, Y²,Y³, and Y⁴ are described as above.

The details of the disclosure are set forth in the accompanyingdescription below. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent disclosure, illustrative methods and materials are nowdescribed. Other features, objects, and advantages of the disclosurewill be apparent from the description and from the claims. In thespecification and the appended claims, the singular forms also includethe plural unless the context clearly dictates otherwise. Unless definedotherwise, all technical and scientific terms used herein have the samemeaning as commonly understood by one of ordinary skill in the art towhich this disclosure belongs. All patents and publications cited inthis specification are incorporated herein by reference in theirentireties.

Definitions

The articles “a” and “an” are used in this disclosure to refer to one ormore than one (e.g., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The term “and/or” is used in this disclosure to mean either “and” or“or” unless indicated otherwise.

The term “optionally substituted” is understood to mean that a givenchemical moiety (e.g., an alkyl group) can (but is not required to) bebonded other substituents (e.g., heteroatoms). For instance, an alkylgroup that is optionally substituted can be a fully saturated alkylchain (e.g. a pure hydrocarbon). Alternatively, the same optionallysubstituted alkyl group can have substituents different from hydrogen.For instance, it can, at any point along the chain be bounded to ahalogen atom, a hydroxyl group, or any other substituent describedherein. Thus the term “optionally substituted” means that a givenchemical moiety has the potential to contain other functional groups,but does not necessarily have any further functional groups.

The term “aryl” refers to cyclic, aromatic hydrocarbon groups that have1 to 2 aromatic rings, including monocyclic or bicyclic groups such asphenyl, biphenyl or naphthyl. Where containing two aromatic rings(bicyclic, etc.), the aromatic rings of the aryl group may be joined ata single point (e.g., biphenyl), or fused (e.g., naphthyl). The arylgroup may be optionally substituted by one or more substituents, e.g., 1to 5 substituents, at any point of attachment. Exemplary substituentsinclude, but are not limited to, —H, -halogen, —O—C₁-C₆ alkyl, —C₁-C₆alkyl, —OC₂-C₆ alkenyl, —OC₂-C₆ alkynyl, —C₂-C₆ alkenyl, —C₂-C₆ alkynyl,—OH, —OP(O)(OH)₂, —OC(O)C₁-C₆ alkyl, —C(O)C₁-C₆ alkyl, —OC(O)OC₁-C₆alkyl, —NH₂, —NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —S(O)₂—C₁-C₆ alkyl,—S(O)NHC₁-C₆ alkyl, and —S(O)N(C₁-C₆ alkyl)₂. The substituents canthemselves be optionally substituted. Furthermore when containing twofused rings the aryl groups herein defined may have an unsaturated orpartially saturated ring fused with a fully saturated ring. Exemplaryring systems of these aryl groups include indanyl, indenyl,tetrahydronaphthalenyl, and tetrahydrobenzoannulenyl.

Unless otherwise specifically defined, “heteroaryl” means a monovalentmonocyclic aromatic radical of 5 to 24 ring atoms or a polycyclicaromatic radical, containing one or more ring heteroatoms selected fromN, S, P, and O, the remaining ring atoms being C. Heteroaryl as hereindefined also means a bicyclic heteroaromatic group wherein theheteroatom is selected from N, S, P, and O. The aromatic radical isoptionally substituted independently with one or more substituentsdescribed herein. Examples include, but are not limited to, furyl,thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl,isoxazolyl, oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl,quinolyl, benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole,benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl,imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl,indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl,pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl,thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl,indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl,benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl,dihydrobenzothiazine, dihydrobenzoxanyl, quinolinyl, isoquinolinyl,1,6-naphthyridinyl, benzo[de]isoquinolinyl,pyrido[4,3-b][1,6]naphthyridinyl, thieno[2,3-b]pyrazinyl, quinazolinyl,tetrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl,pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-b]pyridinyl,pyrrolo[3,2-b]pyridinyl, imidazo[5,4-b]pyridinyl,pyrrolo[1,2-a]pyrimidinyl, tetrahydro pyrrolo[1,2-a]pyrimidinyl,3,4-dihydro-2H-1λ²-pyrrolo[2,1-b]pyrimidine, dibenzo[b,d] thiophene,pyridin-2-one, furo[3,2-c]pyridinyl, furo[2,3-c]pyridinyl,1H-pyrido[3,4-b][1,4] thiazinyl, benzooxazolyl, benzoisoxazolyl,furo[2,3-b]pyridinyl, benzothiophenyl, 1,5-naphthyridinyl,furo[3,2-b]pyridine, [1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl, imidazo[1,2-a]pyrimidinyl,[1,2,4]triazolo[4,3-b]pyridazinyl, benzo[c][1,2,5]thiadiazolyl,benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazol-2-one,3,4-dihydro-2H-pyrazolo [1,5-b][1,2]oxazinyl,4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl,imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl,and derivatives thereof. Furthermore when containing two fused rings theheteroaryl groups herein defined may have an unsaturated or partiallysaturated ring fused with a fully saturated ring. Exemplary ring systemsof these heteroaryl groups include indolinyl, indolinonyl,dihydrobenzothiophenyl, dihydrobenzofuran, chromanyl, thiochromanyl,tetrahydroquinolinyl, dihydrobenzothiazine,3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuran, indolinyl, indolyl,and dihydrobenzoxanyl.

“Alkyl” refers to a straight or branched chain saturated hydrocarbon.C₁-C₆ alkyl groups contain 1 to 6 carbon atoms. Examples of a C₁-C₆alkyl group include, but are not limited to, methyl, ethyl, propyl,butyl, pentyl, isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyland neopentyl.

The term “alkenyl” means an aliphatic hydrocarbon group containing acarbon-carbon double bond and which may be straight or branched havingabout 2 to about 6 carbon atoms in the chain. Alkenyl groups can have 2to about 4 carbon atoms in the chain. Branched means that one or morelower alkyl groups such as methyl, ethyl, or propyl are attached to alinear alkenyl chain. Exemplary alkenyl groups include ethenyl,propenyl, n-butenyl, and i-butenyl. A C₂-C₆ alkenyl group is an alkenylgroup containing between 2 and 6 carbon atoms.

The term “alkynyl” means an aliphatic hydrocarbon group containing acarbon-carbon triple bond and which may be straight or branched havingabout 2 to about 6 carbon atoms in the chain. Alkynyl groups can have 2to about 4 carbon atoms in the chain. Branched means that one or morelower alkyl groups such as methyl, ethyl, or propyl are attached to alinear alkynyl chain. Exemplary alkynyl groups include ethynyl,propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, and n-pentynyl. A C₂-C₆alkynyl group is an alkynyl group containing between 2 and 6 carbonatoms.

The term “cycloalkyl” means monocyclic or polycyclic saturated carbonrings containing 3-18 carbon atoms. Examples of cycloalkyl groupsinclude, without limitations, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptanyl, cyclooctanyl, norboranyl, norborenyl,bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl. A C₃-C₈ cycloalkyl is acycloalkyl group containing between 3 and 8 carbon atoms. A cycloalkylgroup can be fused (e.g., decalin) or bridged (e.g., norbornane).

The term “cycloalkenyl” means monocyclic, non-aromatic unsaturatedcarbon rings containing 4-18 carbon atoms. Examples of cycloalkenylgroups include, without limitation, cyclopentenyl, cyclohexenyl,cycloheptenyl, cyclooctenyl, and norborenyl. A C₄-C₈ cycloalkenyl is acycloalkenyl group containing between 4 and 8 carbon atoms.

The terms “heterocyclyl” or “heterocycloalkyl” or “heterocycle” refer tomonocyclic or polycyclic 3 to 24-membered rings containing carbon andheteroatoms taken from oxygen, nitrogen, or sulfur and wherein there isnot delocalized π electrons (aromaticity) shared among the ring carbonor heteroatoms. Heterocyclyl rings include, but are not limited to,oxetanyl, azetadinyl, tetrahydrofuranyl, pyrrolidinyl, oxazolinyl,oxazolidinyl, thiazolinyl, thiazolidinyl, pyranyl, thiopyranyl,tetrahydropyranyl, dioxalinyl, piperidinyl, morpholinyl,thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S-dioxide,piperazinyl, azepinyl, oxepinyl, diazepinyl, tropanyl, and homotropanyl.A heterocyclyl or heterocycloalkyl ring can also be fused or bridged,e.g., can be a bicyclic ring.

As used herein, the term “halo” or “halogen” means fluoro, chloro,bromo, or iodo.

The term “carbonyl” refers to a functional group composing a carbon atomdouble-bonded to an oxygen atom. It can be abbreviated herein as “oxo”,as C(O), or as C═O.

“Spirocycle” or “spirocyclic” means carbogenic bicyclic ring systemswith both rings connected through a single atom. The ring can bedifferent in size and nature, or identical in size and nature. Examplesinclude spiropentane, spriohexane, spiroheptane, spirooctane,spirononane, or spirodecane. One or both of the rings in a spirocyclecan be fused to another ring carbocyclic, heterocyclic, aromatic, orheteroaromatic ring. One or more of the carbon atoms in the spirocyclecan be substituted with a heteroatom (e.g., O, N, S, or P). A C₃-C₁₂spirocycle is a spirocycle containing between 3 and 12 carbon atoms. Oneor more of the carbon atoms can be substituted with a heteroatom.

The term “spirocyclic heterocycle” or “spiroheterocycle” is understoodto mean a spirocycle wherein at least one of the rings is a heterocycle(e.g., at least one of the rings is furanyl, morpholinyl, orpiperadinyl).

The disclosure also includes pharmaceutical compositions comprising aneffective amount of a disclosed compound and a pharmaceuticallyacceptable carrier. Representative “pharmaceutically acceptable salts”include, e.g., water-soluble and water-insoluble salts, such as theacetate, amsonate (4,4-diaminostilbene-2,2-disulfonate),benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate,bromide, butyrate, calcium, calcium edetate, camsylate, carbonate,chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate,estolate, esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, sethionate,lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, N-methylglucamine ammonium salt,3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate(1,1-methene-bis-2-hydroxy-3-naphthoate, einbonate), pantothenate,phosphate/diphosphate, picrate, polygalacturonate, propionate,p-toluenesulfonate, salicylate, stearate, subacetate, succinate,sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate,tosylate, triethiodide, and valerate salts.

The term “stereoisomers” refers to the set of compounds which have thesame number and type of atoms and share the same bond connectivitybetween those atoms, but differ in three dimensional structure. The term“stereoisomer” refers to any member of this set of compounds.

The term “diastereomers” refers to the set of stereoisomers which cannotbe made superimposable by rotation around single bonds. For example,cis- and trans-double bonds, endo- and exo-substitution on bicyclic ringsystems, and compounds containing multiple stereogenic centers withdifferent relative configurations are considered to be diastereomers.The term “diastereomer” refers to any member of this set of compounds.In some examples presented, the synthetic route may produce a singlediastereomer or a mixture of diastereomers. In some cases thesediastereomers were separated and in other cases a wavy bond is used toindicate the structural element where configuration is variable.

The term “enantiomers” refers to a pair of stereoisomers which arenon-superimposable mirror images of one another. The term “enantiomer”refers to a single member of this pair of stereoisomers. The term“racemic” refers to a 1:1 mixture of a pair of enantiomers.

The term “tautomers” refers to a set of compounds that have the samenumber and type of atoms, but differ in bond connectivity and are inequilibrium with one another. A “tautomer” is a single member of thisset of compounds. Typically a single tautomer is drawn but it isunderstood that this single structure is meant to represent all possibletautomers that might exist. Examples include enol-ketone tautomerism.When a ketone is drawn it is understood that both the enol and ketoneforms are part of the disclosure.

An “effective amount” when used in connection with a compound is anamount effective for treating or preventing a disease in a subject asdescribed herein.

The term “carrier”, as used in this disclosure, encompasses carriers,excipients, and diluents and means a material, composition or vehicle,such as a liquid or solid filler, diluent, excipient, solvent orencapsulating material, involved in carrying or transporting apharmaceutical agent from one organ, or portion of the body, to anotherorgan, or portion of the body of a subject.

The term “treating” with regard to a subject, refers to improving atleast one symptom of the subject's disorder. Treating includes curing,improving, or at least partially ameliorating the disorder.

The term “disorder” is used in this disclosure to mean, and is usedinterchangeably with, the terms disease, condition, or illness, unlessotherwise indicated.

The term “administer”, “administering”, or “administration” as used inthis disclosure refers to either directly administering a disclosedcompound or pharmaceutically acceptable salt of the disclosed compoundor a composition to a subject, or administering a prodrug derivative oranalog of the compound or pharmaceutically acceptable salt of thecompound or composition to the subject, which can form an equivalentamount of active compound within the subject's body.

The term “prodrug,” as used in this disclosure, means a compound whichis convertible in vivo by metabolic means (e.g., by hydrolysis) to adisclosed compound. Furthermore, as used herein a prodrug is a drugwhich is inactive in the body, but is transformed in the body typicallyeither during absorption or after absorption from the gastrointestinaltract into the active compound. The conversion of the prodrug into theactive compound in the body may be done chemically or biologically(e.g., using an enzyme).

The term “solvate” refers to a complex of variable stoichiometry formedby a solute and solvent. Such solvents for the purpose of the disclosuremay not interfere with the biological activity of the solute. Examplesof suitable solvents include, but are not limited to, water, MeOH, EtOH,and AcOH. Solvates wherein water is the solvent molecule are typicallyreferred to as hydrates. Hydrates include compositions containingstoichiometric amounts of water, as well as compositions containingvariable amounts of water.

The term “isomer” refers to compounds that have the same composition andmolecular weight but differ in physical and/or chemical properties. Thestructural difference may be in constitution (geometric isomers) or inthe ability to rotate the plane of polarized light (stereoisomers). Withregard to stereoisomers, the compounds of Formula I may have one or moreasymmetric carbon atom and may occur as racemates, racemic mixtures andas individual enantiomers or diastereomers.

A “patient” or “subject” is a mammal, e.g., a human, mouse, rat, guineapig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey,chimpanzee, baboon or rhesus.

In another embodiment of the disclosure are described compounds of theFormula IA:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,tautomers or isomer thereof; where R, L, X¹, X², X³, X⁴, Y¹, Y³, and Y⁴are defined as above in Formula I.

In another embodiment of the compounds of Formula IA, X⁴ is CR¹R².

In another embodiment of the compounds of Formula IA, X¹ is NR³, O, orC═O.

In another embodiment of the compounds of Formula IA, X¹ is O.

In another embodiment of the compounds of Formula IA, X¹ is O and X⁴ isCR¹R².

In some embodiments of the disclosure, the compounds of Formula IA maybe of the Formula IA-1:

For instance, in some embodiments of Formula IA-1, the compounds can beof the Formula IA-1a, Formula IA-1b, Formula IA-1c, Formula IA-1d,Formula IA-1e, or Formula IA-1f:

In other embodiments of the compounds of Formula IA, the compound is ofthe Formula IA-2:

In yet other another embodiments of the compounds of Formula IA, thecompound is of the Formula IA-3:

In yet other embodiments of the compounds of Formula IA, the compound isof the Formula IA-4:

In yet other another embodiments of the compounds of Formula IA, thecompound is of the Formula IA-5:

In yet other another embodiments of the compounds of Formula IA, thecompound is of the Formula IA-6:

In yet other another embodiments of the compounds of Formula IA, thecompound is of the Formula IA-7:

In other embodiments of the compounds of Formula IA, the compound mayalso be of the Formula IA-8:

In other embodiments of the compounds of Formula IA, the compound is ofthe Formula IA-9:

In a further embodiment of the compounds of Formula IA, the compound isalso of the Formula IA-10:

In another embodiment of the compounds of Formula IA, the compound is ofthe Formula IA-11:

In one embodiment of the disclosure are also disclosed compounds of theFormula IB:

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,enantiomers and isomers thereof where R, L, X¹, X², X³, X⁴, Y¹, Y², andY⁴ are defined as above in Formula I.

In one embodiment of the compounds of Formula IB, X⁴ is CR¹R².

In another embodiment of the compounds of Formula IB, X¹ is NR³, O, orC═O.

In another embodiment of the compounds of Formula IB, X¹ is O.

In another embodiment of the compounds of Formula IB, X¹ is O and X⁴ isCR¹R².

In another embodiment of the compounds of Formula IB, X¹ is N, X² isC═O, and X⁴ is CR¹R².

In some embodiments of the disclosure, the compounds of Formula IB, maybe of the Formula IB-1:

In other embodiments of the compounds of Formula IB, the compound is ofthe Formula IB-2:

For instance, in some embodiments, the compounds of the disclosure canbe of the Formula IB-2a:

In yet other embodiments of the compounds of Formula IB, the compound isof the Formula (IB-3):

In other embodiments of the compounds of Formula IB, the compound mayalso be of the Formula IB-4:

In other embodiments of the compounds of Formula IB, the compound is ofthe Formula (IB-5):

In some embodiments of Formula (I), X¹ is O. In another embodiment, X¹is O and X² is CR¹R². In yet another embodiment, X¹ is O, X² is CR¹R²,and X³ is CR^(1′)R^(2′). In another embodiment, X¹ is O, X² is CR¹R², X³is CR^(1′)R^(2′), and X⁴ is CR¹R². In yet another embodiment, X¹ is O,X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², and Y¹ is CR¹. In anotherembodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹is CR¹, and Y³ is CR¹. In yet another embodiment, X¹ is O, X² is CR¹R²,X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is CR¹, and Y⁴ is CR¹.In another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is CR¹, and Y² is C.

In another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, and Y³ is C. In yet another embodiment, X¹ is O, X² isCR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is C, and Y⁴ isCR¹. In another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′),X⁴ is CR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is CR¹, and Y² is CR¹.

In another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is CR¹, Y² is C, and L is a bond. In yetanother embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is CR¹, Y² is C, and L is —C(O)O—. Inyet another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is CR¹, Y² is C, and L is —C(O)NR³—. Inanother embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is CR¹, Y² is C, and L is —S(O)₂—. Inyet another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is CR¹, Y² is C, and L is —S(O)₂NR³—.

In another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is CR¹, Y² is CR¹, and L is a bond. In yetanother embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is CR¹, Y² is CR¹, and L is —C(O)O—. Inyet another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is CR¹, Y² is CR¹, and L is —C(O)NR³—. Inanother embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is CR¹, Y² is CR¹, and L is —S(O)₂—. Inyet another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is CR¹, Y² is CR¹, and L is —S(O)₂NR³—.

In another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², and Y¹ is N. In yet another embodiment, X¹ is O, X² is CR¹R², X³is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, and Y³ is CR¹. In anotherembodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹is N, Y³ is CR¹, and Y⁴ is CR¹. In yet another embodiment, X¹ is O, X²is CR¹R², X³ is CR¹R², X⁴ is CR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is CR¹, andY² is C.

In another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, and Y³ is C. In yet another embodiment, X¹ is O, X² isCR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is C, and Y⁴ isCR¹. In another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′),X⁴ is CR¹R², Y¹ is N, Y³ is C, Y⁴ is CR¹, and Y² is CR¹.

In another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is CR¹, Y² is C, and L is a bond. In yetanother embodiment, X¹ is O, X² is CR¹R², X³ is CR¹R², X⁴ is CR¹R², Y¹is N, Y³ is CR¹, Y⁴ is CR¹, Y² is C, and L is —C(O)O—. In yet anotherembodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹is N, Y³ is CR¹, Y⁴ is CR¹, Y² is C, and L is —C(O)NR³—. In anotherembodiment, X¹ is O, X² is CR¹R², X³ is CR¹R², X⁴ is CR¹R², Y¹ is N, Y³is CR¹, Y⁴ is CR¹, Y² is C, and L is —S(O)₂—. In yet another embodiment,X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ isCR¹, Y⁴ is CR¹, Y² is C, and L is —S(O)₂NR³—.

In another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is C, Y⁴ is CR¹, Y² is CR¹, and L is a bond. In yetanother embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is C, Y⁴ is CR¹, Y² is CR¹, and L is —C(O)O—. In yetanother embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is C, Y⁴ is CR¹, Y² is CR¹, and L is —C(O)NR³—. Inanother embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is C, Y⁴ is CR¹, Y² is CR¹, and L is —S(O)₂—. In yetanother embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is C, Y⁴ is CR¹, Y² is CR¹, and L is —S(O)₂NR³—.

In another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is CR¹, and Y⁴ is N. In yet another embodiment, X¹is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ isCR¹, Y⁴ is N, and Y² is C. In another embodiment, X¹ is O, X² is CR¹R²,X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is C, and Y⁴ is N. Inyet another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is N, and Y² is CR¹.

In another embodiment, X¹ is O, X² is CR¹R², X³ is CR¹R², X⁴ is CR¹R²,Y¹ is CR¹, Y³ is CR¹, Y⁴ is N, Y² is C, and L is a bond. In yet anotherembodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹is CR¹, Y³ is CR¹, Y⁴ is N, Y² is C, and L is —C(O)O—. In yet anotherembodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹is CR¹, Y³ is CR¹, Y⁴ is N, Y² is C, and L is —C(O)NR³—. In anotherembodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹is CR¹, Y³ is CR¹, Y⁴ is N, Y² is C, and L is —S(O)₂—. In yet anotherembodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹is CR¹, Y³ is CR¹, Y⁴ is N, Y² is C, and L is —S(O)₂NR³—.

In another embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is N, Y² is CR¹, and L is a bond. In yetanother embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is N, Y² is CR¹, and L is —C(O)O—. In yetanother embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is N, Y² is CR¹, and L is —C(O)NR³—. Inanother embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is N, Y² is CR¹, and L is —S(O)₂—. In yetanother embodiment, X¹ is O, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is N, Y² is CR¹, and L is —S(O)₂NR³—.

In some embodiments of Formula (I), X¹ is NR³. In another embodiment, X¹is NR³ and X² is CR¹R². In yet another embodiment, X¹ is NR³, X² isCR¹R², and X³ is CR^(1′)R^(2′). In another embodiment, X¹ is NR³, X² isCR¹R², X³ is CR^(1′)R^(2′), and X⁴ is CR¹R². In yet another embodiment,X¹ is NR³, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², and Y¹ is CR¹.In another embodiment, X¹ is NR³, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴is CR¹R², Y¹ is CR¹, and Y³ is CR¹. In yet another embodiment, X¹ isNR³, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ isCR¹, and Y⁴ is CR¹. In another embodiment, X¹ is NR³, X² is CR¹R², X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is CR¹, and Y² isC.

In another embodiment, X¹ is NR³, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴is CR¹R², Y¹ is CR¹, and Y³ is C. In yet another embodiment, X¹ is NR³,X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is C, andY⁴ is CR¹. In another embodiment, X¹ is NR³, X² is CR¹R², X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is CR¹, and Y² isCR¹.

In another embodiment, X¹ is NR³, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴is CR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is CR¹, Y² is C, and L is a bond. Inyet another embodiment, X¹ is NR³, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴is CR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is CR¹, Y² is C, and L is —C(O)O—. Inyet another embodiment, X¹ is NR³, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴is CR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is CR¹, Y² is C, and L is —C(O)NR³—.In another embodiment, X¹ is NR³, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴is CR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is CR¹, Y² is C, and L is —S(O)₂—. Inyet another embodiment, X¹ is NR³, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴is CR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is CR¹, Y² is C, and L is —S(O)₂NR³—.

In another embodiment, X¹ is NR³, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴is CR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is CR¹, Y² is CR¹, and L is a bond. Inyet another embodiment, X¹ is NR³, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴is CR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is CR¹, Y² is CR¹, and L is —C(O)O—. Inyet another embodiment, X¹ is NR³, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴is CR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is CR¹, Y² is CR¹, and L is —C(O)NR³—.In another embodiment, X¹ is NR³, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴is CR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is CR¹, Y² is CR¹, and L is —S(O)₂—. Inyet another embodiment, X¹ is NR³, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴is CR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is CR¹, Y² is CR¹, and L is —S(O)₂NR³—.

In another embodiment, X¹ is NR³, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴is CR¹R², and Y¹ is N. In yet another embodiment, X¹ is NR³, X² isCR¹R², X³ is CR¹R², X⁴ is CR¹R², Y¹ is N, and Y³ is CR¹. In anotherembodiment, X¹ is NR³, X² is CR¹R², X³ is CR¹R², X⁴ is CR¹R², Y¹ is N,Y³ is CR¹, and Y⁴ is CR¹. In yet another embodiment, X¹ is NR³, X² isCR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is CR¹,and Y² is C.

In another embodiment, X¹ is NR³, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴is CR¹R², Y¹ is N, and Y³ is C. In yet another embodiment, X¹ is NR³, X²is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is C, and Y⁴ isCR¹. In another embodiment, X¹ is NR³, X² is CR¹R², X³ is CR^(1′)R^(2′),X⁴ is CR¹R², Y¹ is N, Y³ is C, Y⁴ is CR¹, and Y² is CR¹.

In another embodiment, X¹ is NR³, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴is CR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is CR¹, Y² is C, and L is a bond. Inyet another embodiment, X¹ is NR³, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴is CR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is CR¹, Y² is C, and L is —C(O)O—. Inyet another embodiment, X is NR³, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴is CR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is CR¹, Y² is C, and L is —C(O)NR³—. Inanother embodiment, X¹ is NR³, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is CR¹, Y² is C, and L is —S(O)₂—. In yetanother embodiment, X¹ is NR³, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is CR¹, Y² is C, and L is —S(O)₂NR³—.

In another embodiment, X¹ is NR³, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴is CR¹R², Y¹ is N, Y³ is C, Y⁴ is CR¹, Y² is CR¹, and L is a bond. Inyet another embodiment, X¹ is NR³, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴is CR¹R², Y¹ is N, Y³ is C, Y⁴ is CR¹, Y² is CR¹, and L is —C(O)O—. Inyet another embodiment, X¹ is NR³, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴is CR¹R², Y¹ is N, Y³ is C, Y⁴ is CR¹, Y² is CR¹, and L is —C(O)NR³—. Inanother embodiment, X¹ is NR³, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is C, Y⁴ is CR¹, Y² is CR¹, and L is —S(O)₂—. In yetanother embodiment, X¹ is NR³, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is C, Y⁴ is CR¹, Y² is CR¹, and L is —S(O)₂NR³—.

In another embodiment, X¹ is NR³, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴is CR¹R², Y¹ is CR¹, Y³ is CR¹, and Y⁴ is N. In yet another embodiment,X¹ is NR³, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³is CR¹, Y⁴ is N, and Y² is C. In another embodiment, X¹ is NR³, X² isCR¹R², X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is C, and Y⁴ isN. In yet another embodiment, X¹ is NR³, X² is CR¹R², X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is N, and Y² is CR¹.

In another embodiment, X¹ is NR³, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴is CR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is N, Y² is C, and L is a bond. Inyet another embodiment, X¹ is NR³, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴is CR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is N, Y² is C, and L is —C(O)O—. Inyet another embodiment, X¹ is NR³, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴is CR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is N, Y² is C, and L is —C(O)NR³—. Inanother embodiment, X¹ is NR³, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is N, Y² is C, and L is —S(O)₂—. In yetanother embodiment, X¹ is NR³, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is N, Y² is C, and L is —S(O)₂NR³—.

In another embodiment, X¹ is NR³, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴is CR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is N, Y² is CR¹, and L is a bond. Inyet another embodiment, X¹ is NR³, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴is CR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is N, Y² is CR¹, and L is —C(O)O—. Inyet another embodiment, X¹ is NR³, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴is CR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is N, Y² is CR¹, and L is —C(O)NR³—. Inanother embodiment, X¹ is NR³, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is N, Y² is CR¹, and L is —S(O)₂—. In yetanother embodiment, X¹ is NR³, X² is CR¹R², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is N, Y² is CR¹, and L is —S(O)₂NR³—.

In some embodiments of Formula (I), X¹ is NR³. In another embodiment, X¹is NR³ and X² is C═O. In yet another embodiment, X¹ is NR³, X² is C═O,and X³ is CR^(1′)R^(2′). In another embodiment, X¹ is NR³, X² is C═O, X³is CR^(1′)R^(2′), and X⁴ is CR¹R². In yet another embodiment, X¹ is NR³,X² is C═O, X³ is CR^(1′)R^(2′), X⁴ is CR¹R², and Y¹ is CR¹. In anotherembodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹is CR¹, and Y³ is CR¹. In yet another embodiment, X¹ is NR³, X² is C═O,X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is CR¹, and Y⁴ is CR¹.In another embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is CR¹, and Y² is C.

In another embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, and Y³ is C. In yet another embodiment, X is NR³, X²is C═O, X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is C, and Y⁴ isCR¹. In another embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′),X⁴ is CR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is CR¹, and Y² is CR¹.

In another embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is CR¹, Y² is C, and L is a bond. In yetanother embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is CR¹, Y² is C, and L is —C(O)O—. Inyet another embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is CR¹, Y² is C, and L is —C(O)NR³—. Inanother embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is CR¹, Y² is C, and L is —S(O)₂—. Inyet another embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ is CR¹, Y² is C, and L is —S(O)₂NR³—.

In another embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is CR¹, Y² is CR¹, and L is a bond. In yetanother embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is CR¹, Y² is CR¹, and L is —C(O)O—. Inyet another embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is CR¹, Y² is CR¹, and L is —C(O)NR³—. Inanother embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is CR¹, Y² is CR¹, and L is —S(O)₂—. Inyet another embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is CR¹, Y² is CR¹, and L is —S(O)₂NR³—.

In another embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², and Y¹ is N. In yet another embodiment, X¹ is NR³, X² is C═O, X³is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, and Y³ is CR¹. In anotherembodiment, X¹ is NR³, X² is C═O, X³ is CR¹R², X⁴ is CR¹R², Y¹ is N, Y³is CR¹, and Y⁴ is CR¹. In yet another embodiment, X¹ is NR³, X² is C═O,X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is CR¹, and Y²is C.

In another embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, and Y³ is C. In yet another embodiment, X¹ is NR³, X² isC═O, X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is N, Y³ is C, and Y⁴ is CR¹.In another embodiment, X¹ is NR³, X² is C═O, X³ is CR¹R², X⁴ is CR¹R²,Y¹ is N, Y³ is C, Y⁴ is CR¹, and Y² is CR¹.

In another embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is CR¹, Y² is C, and L is a bond. In yetanother embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is CR¹, Y² is C, and L is —C(O)O—. In yetanother embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is CR¹, Y² is C, and L is —C(O)NR³—. Inanother embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is CR¹, Y² is C, and L is —S(O)₂—. In yetanother embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is CR¹, Y⁴ is CR¹, Y² is C, and L is —S(O)₂NR³—.

In another embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is C, Y⁴ is CR¹, Y² is CR¹, and L is a bond. In yetanother embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is C, Y⁴ is CR¹, Y² is CR¹, and L is —C(O)O—. In yetanother embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is C, Y⁴ is CR¹, Y² is CR¹, and L is —C(O)NR³—. Inanother embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is C, Y⁴ is CR¹, Y² is CR¹, and L is —S(O)₂—. In yetanother embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is N, Y³ is C, Y⁴ is CR¹, Y² is CR¹, and L is —S(O)₂NR³—.

In another embodiment, X¹ is NR³, X² is C═O², X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is CR¹, and Y⁴ is N. In yet another embodiment, X¹is NR³, X² is C═O, X³ is CR¹R², X⁴ is CR¹R², Y¹ is CR¹, Y³ is CR¹, Y⁴ isN, and Y² is C. In another embodiment, X¹ is NR³, X² is C═O, X³ isCR^(1′)R^(2′), X⁴ is CR¹R², Y¹ is CR¹, Y³ is C, and Y⁴ is N. In yetanother embodiment, X¹ is NR³, X² is C═O, X³ is CR¹R², X⁴ is CR¹R², Y¹is CR¹, Y³ is C, Y⁴ is N, and Y² is CR¹.

In another embodiment, X¹ is NR³, X² is C═O, X³ is CR¹R², X⁴ is CR¹R²,Y¹ is CR¹, Y³ is CR¹, Y⁴ is N, Y² is C, and L is a bond. In yet anotherembodiment, X¹ is NR³, X² is C═O, X³ is CR¹R², X⁴ is CR¹R², Y¹ is CR¹,Y³ is CR¹, Y⁴ is N, Y² is C, and L is —C(O)O—. In yet anotherembodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹is CR¹, Y³ is CR¹, Y⁴ is N, Y² is C, and L is —C(O)NR³—. In anotherembodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹is CR¹, Y³ is CR¹, Y⁴ is N, Y² is C, and L is —S(O)₂—. In yet anotherembodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹is CR¹, Y³ is CR¹, Y⁴ is N, Y² is C, and L is —S(O)₂NR³—.

In another embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is N, Y² is CR¹, and L is a bond. In yetanother embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is N, Y² is CR¹, and L is —C(O)O—. In yetanother embodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ isCR¹R², Y¹ is CR¹, Y³ is C, Y⁴ is N, Y² is CR¹, and L is —C(O)NR³—. Inanother embodiment, X¹ is NR³, X² is C═O, X³ is CR¹R², X⁴ is CR¹R², Y¹is CR¹, Y³ is C, Y⁴ is N, Y² is CR¹, and L is —S(O)₂—. In yet anotherembodiment, X¹ is NR³, X² is C═O, X³ is CR^(1′)R^(2′), X⁴ is CR¹R², Y¹is CR¹, Y³ is C, Y⁴ is N, Y² is CR¹, and L is —S(O)₂NR³—.

In some embodiments of Formula (I), X² is CR¹R²; R¹ is —H or —C₁-C₆alkyl; and R² is —H, aryl, or —C₁-C₆ alkyl optionally substituted withone or more —OH, halogen, or —OR³.

In some embodiments of Formula (I), X³ is CR^(1′)R^(2′); R¹ is —H or—C₁-C₆ alkyl; and

R^(2′) is —H, or —C₁-C₆ alkyl optionally substituted with one or morehalogen, —OR³, or aryl.

In some embodiments of Formula (I), X³ is CR^(1′)R^(2′) and R^(1′) andR^(2′) combine with the carbon atom to which they are both attached toform a spirocycle.

In some embodiments of Formula (I), R¹ and R² combine with the atom towhich they are both attached to form a spirocycle. In anotherembodiment, R¹ and R² combine with the atom to which they are bothattached to form a spiroheterocycle. In another embodiment, R¹ and R²combine with the atom to which they are both attached to form aspirocycloalkenyl.

In some embodiments of Formula (I), R¹ and R², when on adjacent atoms,combine to form a heterocycle. In another embodiment, R¹ and R², when onadjacent atoms, combine to form a cycloalkyl. In yet another embodiment,R¹ and R², when on adjacent atoms, combine to form a cycloalkenyl. Inanother embodiment, R¹ and R², when on adjacent atoms, combine to forman aryl. In yet another embodiment, R¹ and R², when on adjacent atoms,combine to form a heteroaryl containing 1 to 5 heteroatoms selected fromthe group consisting of N, S, P, and O.

In some embodiments of Formula (I), R¹ and R², when on non-adjacentatoms, combine to form a bridging cycloalkyl. In yet another embodiment,R¹ and R², when on non-adjacent atoms, combine to form aheterocycloalkyl.

In some embodiments of Formula (I), R^(1′) and R^(2′) combine with theatom to which they are both attached to form a spirocycle. In anotherembodiment, R^(1′) and R^(2′) combine with the atom to which they areboth attached to form a spiroheterocycle. In another embodiment, R¹ andR^(2′) combine with the atom to which they are both attached to form aspirocycloalkenyl.

In some embodiments of Formula (I), R^(1′) and R^(2′), when onnon-adjacent atoms, combine to form a bridging cycloalkyl. In yetanother embodiment, R^(1′) and R^(2′), when on non-adjacent atoms,combine to form a heterocycloalkyl.

In some embodiments of Formula (I), R³ and R combine with the nitrogenatom to which they are attached to form a heterocycle optionallysubstituted with —R⁴, —OR⁴, or —NR⁴R⁵. In some embodiments of Formula(I), R³ and R combine with the nitrogen atom to which they are attachedto form a heteroaryl containing 1 to 5 heteroatoms selected from thegroup consisting of N, S, P, and O, optionally substituted with —R⁴,—OR⁴, or —NR⁴R⁵.

In some embodiments of Formula (I), n is 1 to 6. In another embodiment,n is 0 to 5. In yet another embodiment, n is 0 to 4. In yet anotherembodiment, n is 1 to 4. In another embodiment, n is 0 to 3. In yetanother embodiment, n is 0 to 2. In yet another embodiment, n is 0 or 1.In another embodiment, n is 1 or 2.

In some embodiments of Formula (I), X⁴, X², and X¹ are not allsimultaneously CR¹R².

In some embodiments of Formula (I), X¹ is O, X² is CR¹R², and X⁴ isCR¹R². In another embodiment, X² is C═O, X⁴ is C═O, and X¹ is CR¹R². Inyet another embodiment, X¹ is NR³, X² is C═O, and X⁴ is CR¹R².

In an illustrative embodiment, the compound of Formula I is:

-   4-(benzo[d]oxazol-2-yl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(1-(cyclohexylmethyl)-1H-benzo[d]imidazol-2-yl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(benzo[d]thiazol-2-yl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(cyclohexylmethyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(4-cyano-3-(trifluoromethyl)phenyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(3,4-dichlorophenyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(pyridin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(pyridin-3-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(pyridin-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(p-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(piperidine-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-methoxyphenyl    8-(hydroxycarbamoyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate;-   cyclohexyl    8-(hydroxycarbamoyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate;-   N-hydroxy-4-(piperidin-1-yl    sulfonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N8-hydroxy-N4-methyl-N4-phenyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide;-   4-cyclohexyl-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(2-(dimethylamino)ethyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(2-methoxyethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-benzo[d]imidazol-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N8-hydroxy-N4-(4-methoxyphenyl)-2-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide;-   (R)—N-hydroxy-4-((4-methoxyphenyl)sulfonyl)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-4-(4-methoxybenzyl)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-2-methyl-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-2,4-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N8-hydroxy-N4-(4-methoxyphenyl)-2-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide;-   (S)—N-hydroxy-4-((4-methoxyphenyl)sulfonyl)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-2-methyl-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-2,4-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(4-methoxybenzyl)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-3,3-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-3,3,4-trimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-3-isopropyl-4-(4-methoxybenzyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-3-isopropyl-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N8-hydroxy-3-isopropyl-N4-(4-methoxyphenyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide;-   (R)—N-hydroxy-3-isopropyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-3-isopropyl-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-isopropyl-4-(4-methoxybenzyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-isopropyl-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N8-hydroxy-3-isopropyl-N4-(4-methoxyphenyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide;-   (S)—N-hydroxy-3-isopropyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-isopropyl-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-3,4-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N8-hydroxy-N4-(4-methoxyphenyl)-3-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide;-   (R)—N-hydroxy-4-((4-methoxyphenyl)sulfonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-4-(4-methoxybenzyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-3-methyl-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N8-hydroxy-N4-(4-methoxyphenyl)-3-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide;-   (S)—N-hydroxy-4-((4-methoxyphenyl)sulfonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(4-methoxybenzyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-methyl-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3,4-dimethyl-2,3,4,5-tetrahydrobenzo[1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-4-(4-methoxybenzyl)-5-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carboxamide;-   (S)—N-hydroxy-4-(4-methoxybenzyl)-5-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carboxamide;-   N8-hydroxy-N4-(4-methoxyphenyl)-2,3-dihydropyrido[2,3-f][1,4]oxazepine-4,8(5H)-dicarboxamide;-   N-hydroxy-4-((4-methoxyphenyl)sulfonyl)-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(4-methoxybenzyl)-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine-8-carboxamide;-   N8-hydroxy-N4-(4-methoxyphenyl)-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4,8(5H)-dicarboxamide;-   N-hydroxy-4-((4-methoxyphenyl)sulfonyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(4-methoxybenzyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(4-methoxybenzyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(4-methoxyphenethyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(4-methoxybenzyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carboxamide;-   N-hydroxy-4-(4-methoxyphenethyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carboxamide;-   N-hydroxy-4-(4-methoxyphenethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-8-carboxamide;-   4-((1H-benzo[d]imidazol-2-yl)methyl)-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-8-carboxamide;-   4-((1H-benzo[d]imidazol-2-yl)methyl)-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   N-hydroxy-4-(4-methoxyphenethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   N-hydroxy-2-oxo-4-(1-phenylethyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   N-hydroxy-4-(4-methoxybenzyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   N-hydroxy-4-((4-methoxyphenyl)sulfonyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   N-hydroxy-2-oxo-4-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   N-hydroxy-4-(4-methoxybenzyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   N-hydroxy-4-(4-methoxybenzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   N-hydroxy-4-(4-methoxybenzyl)-1-methyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   2-benzyl-N-hydroxy-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine-8-carboxamide    1,1-dioxide;-   2-benzyl-N-hydroxy-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine-7-carboxamide    1,1-dioxide;-   N8-hydroxy-N4-(4-methoxyphenyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide;-   N7-hydroxy-N4-(4-methoxyphenyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4,7(5H)-dicarboxamide;-   N-hydroxy-4-((4-methoxyphenyl)sulfonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-((4-methoxyphenyl)sulfonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carboxamide;-   4-((1H-benzo[d]imidazol-2-yl)methyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-((1H-benzo[d]imidazol-2-yl)methyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carboxamide;-   N-hydroxy-4-((1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)methyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-((1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)methyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carboxamide;-   N-hydroxy-4-(4-methoxyphenethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(4-methoxyphenethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carboxamide;-   N-hydroxy-4-(4-methoxybenzyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(4-methoxybenzyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carboxamide;-   4-(1H-benzo[d]imidazol-2-yl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   4-(1H-benzo[d]imidazol-2-yl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carboxamide;-   N-hydroxy-4-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(1-(2-methoxyethyl)-1H-benzo[d]imidazol-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carboxamide;-   N-hydroxy-4-((5-isopropylpyridin-2-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   N-hydroxy-2-oxo-4-(pyridin-4-ylmethyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   N-hydroxy-2-oxo-4-(pyridin-2-ylmethyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   N-hydroxy-2-oxo-4-(thiazol-2-ylmethyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   N-hydroxy-4-(4-isopropoxybenzyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   N-hydroxy-2-oxo-4-(4-(trifluoromethoxy)benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   N-hydroxy-2-oxo-4-(3-phenoxybenzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   N-hydroxy-2-oxo-4-(4-phenoxybenzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   N-hydroxy-2-oxo-4-(3-(trifluoromethoxy)benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   N-hydroxy-2-oxo-4-(2-(trifluoromethoxy)benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   N-hydroxy-2-oxo-4-(4-(pyridin-2-yl)benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   4-(4-(1H-pyrazol-1-yl)benzyl)-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   4-(4-cyanobenzyl)-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   N-hydroxy-2-oxo-4-(pyrimidin-5-ylmethyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   N-hydroxy-4-(naphthalen-1-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   4-((2-(3-fluorophenyl)oxazol-4-yl)methyl)-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   4-(3-((dimethylamino)methyl)benzyl)-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   4-benzyl-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   N-hydroxy-4-(4-isopropylbenzyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   4-(4-chlorobenzyl)-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   4-(2,5-difluorobenzyl)-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   4-(3,5-difluorobenzyl)-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   4-(3,5-dichlorobenzyl)-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   4-(2-fluoro-4-methoxybenzyl)-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   4-(2-chlorobenzyl)-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   4-((2,2-difluorobenzo[d][1,3]dioxol-4-yl)methyl)-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   N-hydroxy-2-oxo-4-(pyridin-3-ylmethyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   N-hydroxy-4-((1-methyl-1H-imidazol-2-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   4-((1-acetylpiperidin-3-yl)methyl)-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   N-hydroxy-4-(imidazo[1,2-a]pyridin-2-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   4-(cyclopropylmethyl)-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   N-hydroxy-2-oxo-4-((tetrahydrofuran-3-yl)methyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   4-((4,5-dimethylthiazol-2-yl)methyl)-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   4-(3-chlorobenzyl)-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   4-(4-(tert-butoxy)benzyl)-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   N-hydroxy-4-((1-isopropylpiperidin-4-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   4-(4-(1H-pyrrol-1-yl)benzyl)-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   N-hydroxy-4-(naphthalen-2-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   N-hydroxy-4-((2-morpholinopyridin-4-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   N-hydroxy-4-(imidazo[1,2-a]pyridin-7-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   N-hydroxy-2-oxo-4-(4-(thiazol-2-yl)benzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   N-hydroxy-4-((6-methoxypyridin-3-yl)methyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-((6-methoxypyridin-3-yl)methyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carboxamide;-   N-hydroxy-4-((5-methoxypyridin-2-yl)methyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-((5-methoxypyridin-2-yl)methyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carboxamide;-   (R)—N8-hydroxy-2-isopropyl-N4-(4-methoxyphenyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide;-   (R)—N8-hydroxy-2-(methoxymethyl)-N4-(4-methoxyphenyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide;-   (S)—N8-hydroxy-2-(methoxymethyl)-N4-(4-methoxyphenyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide;-   (R)—N8-hydroxy-N4-(4-methoxyphenyl)-2-phenyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide;-   (S)—N8-hydroxy-N4-(4-methoxyphenyl)-2-phenyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide;-   N-hydroxy-4-methyl-4,5-dihydro-2H-spiro[benzo[f][1,4]oxazepine-3,1′-cyclopropane]-8-carboxamide;-   N-hydroxy-4-phenyl-4,5-dihydro-2H-spiro[benzo[f][1,4]oxazepine-3,1′-cyclopropane]-8-carboxamide;-   N-hydroxy-4-(4-methoxybenzyl)-4,5-dihydro-2H-spiro[benzo[f][1,4]oxazepine-3,1′-cyclopropane]-8-carboxamide;-   (S)-3-ethyl-N-hydroxy-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-3-ethyl-N-hydroxy-4-(4-methoxybenzyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-3-ethyl-N-hydroxy-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-3-ethyl-N-hydroxy-4-(o-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-isopropyl-4-(pyridin-3-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-isopropyl-4-(pyridin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-isopropyl-4-(pyridin-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-methyl-4-(o-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(2-methoxyphenyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-methyl-4-(pyridin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-methyl-4-(pyrrolidine-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-methyl-4-(morpholine-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(isoindoline-2-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(4-methoxypiperidine-1-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-methyl-4-(4-methylpiperazine-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (3S)—N-hydroxy-3-methyl-4-(2-methylpiperidine-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (3S)—N-hydroxy-3-methyl-4-(3-methylmorpholine-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-methyl-4-(oxetan-3-ylmethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-(4-fluorophenyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-(3-fluorophenyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-methyl-4-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   methyl    (S)-8-(hydroxycarbamoyl)-3-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate;-   isopropyl    (S)-8-(hydroxycarbamoyl)-3-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate;-   (S)—N-hydroxy-3-methyl-4-(methylsulfonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-(ethylsulfonyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N8-hydroxy-N4,N4,3-trimethyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide;-   (S)—N-hydroxy-4-((2-methoxyethyl)sulfonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N8-hydroxy-N4-(2-methoxyethyl)-3-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide;-   (S)—N8-hydroxy-3-methyl-N4-phenyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide;-   (S)—N-hydroxy-3-methyl-4-(piperidine-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N8-hydroxy-N4-(2-methoxyethyl)-N4,3-dimethyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide;-   (S)—N-hydroxy-3-methyl-4-(pyridin-3-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-methyl-4-(pyridin-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(3-methoxypropyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (3S)-4-(1-(4-fluorophenyl)ethyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-methyl-4-(3-morpholinopropyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (3S)—N-hydroxy-3-methyl-4-(2-(tetrahydrofuran-2-yl)ethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-ethyl-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-isopropyl-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-isobutyl-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-(cyclobutylmethyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-(cyclopropylmethyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-(4-fluorobenzyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-(cyclohexylmethyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-methyl-4-(2-morpholinoethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(2-methoxyethyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-(cyclopentylmethyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (3S)—N-hydroxy-3-methyl-4-((tetrahydrofuran-2-yl)methyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-cyclopentyl-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-((4-fluorophenyl)sulfonyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   cyclopentyl    (S)-8-(hydroxycarbamoyl)-3-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate;-   cyclohexyl    (S)-8-(hydroxycarbamoyl)-3-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate;-   (S)—N8-hydroxy-N4,3-dimethyl-N4-phenyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide;-   ethyl    (S)-8-(hydroxycarbamoyl)-3-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate;-   cyclobutyl    (S)-8-(hydroxycarbamoyl)-3-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate;-   tetrahydro-2H-pyran-4-yl    (S)-8-(hydroxycarbamoyl)-3-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate;-   4-fluorophenyl    (S)-8-(hydroxycarbamoyl)-3-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate;-   (S)—N-hydroxy-3-methyl-4-(oxetan-3-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-3-(methoxymethyl)-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-4-(4-methoxybenzyl)-3-(methoxymethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-3-(methoxymethyl)-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-3-(methoxymethyl)-4-(o-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-(methoxymethyl)-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(4-methoxybenzyl)-3-(methoxymethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-(methoxymethyl)-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-(methoxymethyl)-4-(o-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamid;-   N-hydroxy-4-(pyrrolidine-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(morpholine-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(4-methylpiperazine-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(4-methoxypiperidine-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(isoindoline-2-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(2-methylpiperidine-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-4-(3-methylmorpholine-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (R)—N-hydroxy-4-(4-methoxybenzyl)-5-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(4-methoxybenzyl)-5-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-methyl-4-(3-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-3-methyl-4-(4-(trifluoromethoxy)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-(4-chlorophenyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-(2-chlorophenyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-(2-fluorophenyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-(azetidine-1-carbonyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N-hydroxy-4-(3-methoxyazetidine-1-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (3S)—N-hydroxy-4-(3-methoxypyrrolidine-1-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)—N8-hydroxy-3-methyl-N4-(pyridin-3-yl)-2,3-dihydrobenzo[f][14]oxazepine-4,8(5H)-dicarboxamide;-   (S)—N4-cyclohexyl-N8-hydroxy-3-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide;-   (S)—N8-hydroxy-3-methyl-N4-(pyridin-2-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide;-   (S)—N8-hydroxy-3-methyl-N4-(tetrahydro-2H-pyran-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide;-   (S)—N8-hydroxy-N4,3-dimethyl-N4-(tetrahydro-2H-pyran-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide;-   (S)—N8-hydroxy-3-methyl-N4-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide;-   (S)-4-((1R,5R)-8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-((1S,5S)-8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (S)-4-(3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   N-hydroxy-2-oxo-4-(piperidine-1-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide;-   (S)-3-benzyl-N-hydroxy-4-(morpholine-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;

In another embodiment, non-limiting illustrative compounds of thedisclosure include:

-   N8-hydroxy-N4-(tetrahydro-2H-pyran-4-yl)-N4-(3-(trifluoromethyl)phenyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide;-   (R)—N-hydroxy-4-(morpholine-4-carbonyl)-3-((trifluoromethoxy)methyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;-   (3S)—N-hydroxy-3,5-dimethyl-4-(morpholine-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide;    or-   (S)-6-fluoro-N-hydroxy-3-methyl-4-(morpholine-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide.

In another embodiment of the disclosure, the compounds of Formula I areenantiomers. In some embodiments the compounds are the (S)-enantiomer.In other embodiments the compounds are the (R)-enantiomer. In yet otherembodiments, the compounds of Formula I may be (+) or (−) enantiomers.

It should be understood that all isomeric forms are included within thepresent disclosure, including mixtures thereof. If the compound containsa double bond, the substituent may be in the E or Z configuration. Ifthe compound contains a disubstituted cycloalkyl, the cycloalkylsubstituent may have a cis- or trans configuration. All tautomeric formsare also intended to be included.

Methods of Synthesizing the Disclosed Compounds

The compounds of the present disclosure may be made by a variety ofmethods, including standard chemistry. Suitable synthetic routes aredepicted in the schemes given below.

The compounds of Formula I may be prepared by methods known in the artof organic synthesis as set forth in part by the following syntheticschemes and examples. In the schemes described below, it is wellunderstood that protecting groups for sensitive or reactive groups areemployed where necessary in accordance with general principles orchemistry. Protecting groups are manipulated according to standardmethods of organic synthesis (T. W. Greene and P. G. M. Wuts,“Protective Groups in Organic Synthesis”, Third edition, Wiley, New York1999). These groups are removed at a convenient stage of the compoundsynthesis using methods that are readily apparent to those skilled inthe art. The selection processes, as well as the reaction conditions andorder of their execution, shall be consistent with the preparation ofcompounds of Formula I.

Those skilled in the art will recognize if a stereocenter exists in thecompounds of Formula I. Accordingly, the present disclosure includesboth possible stereoisomers (unless specified in the synthesis) andincludes not only racemic compounds but the individual enantiomersand/or diastereomers as well. When a compound is desired as a singleenantiomer or diastereomer, it may be obtained by stereospecificsynthesis or by resolution of the final product or any convenientintermediate. Resolution of the final product, an intermediate, or astarting material may be affected by any suitable method known in theart. See, for example, “Stereochemistry of Organic Compounds” by E. L.Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994).

The compounds described herein may be made from commercially availablestarting materials or synthesized using known organic, inorganic, and/orenzymatic processes.

Preparation of Compounds

The compounds of the present disclosure can be prepared in a number ofways well known to those skilled in the art of organic synthesis. By wayof example, compounds of the present disclosure can be synthesized usingthe methods described below, together with synthetic methods known inthe art of synthetic organic chemistry, or variations thereon asappreciated by those skilled in the art. These methods include, but arenot limited, to those methods described below. Compounds of the presentdisclosure can be synthesized by following the steps outlined in GeneralSchemes 1, 2, 3, 4, and 5 which comprise different sequences ofassembling intermediates 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i, 2j, 2k, 2m,2n, 2o, 2p, 2q, 2r, 2s, 2t, 2u, 2v, 2w, 2x, 2y, 2z, 2aa, 2bb, and 2cc.Starting materials are either commercially available or made by knownprocedures in the reported literature or as illustrated.

wherein L, R, R¹, R², R^(1′), R^(2′), Y¹ and Y² are defined as inFormula (I).

The general way of preparing target molecules of Formula (I) by usingintermediates 2a, 2b, 2c, 2d, and 2e is outlined in General Scheme 1.Nucleophilic addition of alcohol 2b to Intermediate 2a using a base,e.g., potassium carbonate (K₂CO₃), in a solvent, e.g., acetonitrile(MeCN), provides Intermediate 2c. Cyclization of Intermediate 2c in thepresence of a catalytic amount of a metal catalyst, e.g., copper iodide(CuI), palladium acetate (Pd(OAc)₂), etc., and a base, e.g., potassiumcarbonate (K₂CO₃), in a solvent, e.g., isopropanol (i-PrOH), optionallyat elevated temperature provides Intermediate 2d. Addition of the R-Lmoiety can be achieved, for instance, via alkylation, reductiveamination, arylation, urea formation, or sulfonation. For example,alkylation of Intermediate 2d with an alkyl halide in the presence of abase, e.g., sodium hydride (NaH), and optionally at elevatedtemperatures provides Intermediate 2e. Treatment of Intermediate 2e withhydroxylamine and a base, e.g., aqueous sodium hydroxide (aq. NaOH) in asolvent, e.g., tetrahydrofuran (THF) and/or methanol (MeOH), providescompounds of Formula (I).

wherein L, R, R^(1′), and R^(2′) are defined as in Formula (I).

The general way of preparing target molecules of Formula (I) by usingintermediates 2f, 2g, 2h, 2i, 2j, and 2k is outlined in General Scheme2. Nucleophilic addition of amine 2g to Intermediate 2f using a base,e.g., N,N-diisopropylethylamine (DIEA), and in a solvent, e.g., MeCN,dichloromethane (DCM), or DMF, provides Intermediate 2h. Protection ofthe amine group in intermediate 2h with a typical acid labile protectinggroup (e.g., t-butoxycarbonyl (Boc)) using a protecting group precursorand 4-Dimethylaminopyridine (DMAP), in a solvent e.g., DCM ortetrahydrofuran (THF), followed by hydrogenation in the presence of ametal catalyst, e.g., palladium on carbon, and hydrogen (H₂) gas in asolvent, e.g., DCM, provides Intermediate 2i. Cyclization ofIntermediate 2i in the presence of a base, e.g., potassium carbonate(K₂CO₃), and in a solvent, e.g., isopropanol (i-PrOH), optionally atelevated temperatures provides Intermediate 2j. Addition of the R-Lmoiety can be achieved via alkylation, reductive amination, arylation,urea formation, or sulfonation. For example, alkylation of Intermediate2j with an alkyl halide in the presence of a base, e.g., sodium hydride(NaH), and optionally at elevated temperatures provides Intermediate 2k.Treatment of Intermediate 2k with hydroxylamine and a base, e.g.,aqueous sodium hydroxide (aq. NaOH) in a solvent, e.g., tetrahydrofuran(THF) and/or methanol (MeOH), provides compounds of Formula (I).

wherein L, R, R^(1′), and R^(2′) are defined as in Formula (I).

The general way of preparing target molecules of Formula (I) by usingintermediates 2m, 2n, 2o, 2p, and 2q, is outlined in General Scheme 3.Sulfonylation of alcohol 2n with Intermediate 2m in the presence of ametal oxide, e.g., MgO, and in a solvent, e.g., THF, providesIntermediate 2o. Cyclization of Intermediate 2o in the presence of abase, e.g., sodium methoxide (NaOMe), and in a solvent, e.g., methanol(MeOH), i-PrOH, etc., provides Intermediate 2p. Addition of the R-Lmoiety can be achieved via alkylation, reductive amination, arylation,urea formation, or sulfonation. For example, alkylation of Intermediate2p with an alkyl halide in the presence of a base, e.g., sodium hydride(NaH), and optionally at elevated temperatures provides Intermediate 2q.Treatment of Intermediate 2q with hydroxylamine and a base, e.g.,aqueous sodium hydroxide (aq. NaOH), in a solvent, e.g., tetrahydrofuran(THF) and/or methanol (MeOH), provides compounds of Formula (I).

wherein L, R, R^(1′), and R^(2′) are defined as in Formula (I).

The general way of preparing target molecules of Formula (I) by usingintermediates 2r, 2s, 2t, 2u, and 2v, is outlined in General Scheme 4.Intermediate 2t can be obtained by alkylation of 2s with phenol 2r usinga Mitsunobu reagent (e.g., diethyl azodicarboxylate (DEAD) ordiisopropyl azodicarboxylate (DIAD)), and triphenyl phosphine in asolvent, e.g., tetrahydrofuran (THF), dichloromethane (DCM).Deprotection of intermediate 2t using a strong acid such astrifluoroacetic acid (TFA) in a solvent, e.g., dichloromethane (DCM),followed by cyclization in the presence of a base, e.g., triethylamine(Et₃N), and optionally in a solvent, e.g., THF, MeOH, etc., at elevatedtemperature provides Intermediate 2u. Addition of the R-L moiety can beachieved via alkylation, reductive amination, arylation, urea formation,or sulfonation. For example, alkylation of Intermediate 2u with an alkylhalide in the presence of a base, e.g., sodium hydride (NaH), andoptionally at elevated temperatures provides Intermediate 2v. Treatmentof Intermediate 2v with hydroxylamine and a base, e.g., aqueous sodiumhydroxide (aq. NaOH) in a solvent, e.g., tetrahydrofuran (THF) and/ormethanol (MeOH), provides compounds of Formula (I).

wherein L, R, R^(1′), and R^(2′) are defined as in Formula (I).

The general way of preparing target molecules of Formula (I) by usingintermediates 2w, 2x, 2y, 2z, 2aa, 2bb, and 2cc, is outlined in GeneralScheme 5. Alkylation of phenol 2w with Intermediate 2x using potassiumiodide (KI) and a base, e.g., potassium carbonate (K₂CO₃), in a solvent,e.g., MeCN, THF, etc., provides Intermediate 2y. Deprotection ofIntermediate 2y using a strong acid such as trifluoroacetic acid (TFA)in a solvent, e.g., dichloromethane (DCM) followed by cyclization viaintramolecular reductive amination in the presence of sodium borohydrideor sodium cyanoborohydride in a solvent, e.g., THF, MeOH, etc., providesIntermediate 2z. Protection of the amine group in intermediate 2z with atypical acid labile protecting group (e.g., t-butoxycarbonyl (Boc))using a protecting group precursor and optionally 4-DMAP in a solvente.g., DCM or tetrahydrofuran (THF), followed by carbonylation in thepresence of a metal catalyst, e.g.,[1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride, andcarbon monoxide (CO) gas in a solvent, e.g., DCM, provides Intermediate2aa. Deprotection of intermediate 2aa using a strong acid such astrifluoroacetic acid (TFA) in a solvent, e.g., dichloromethane (DCM)provides Intermediate 2bb. Addition of the R-L moiety can be achievedvia alkylation, reductive amination, arylation, urea formation, orsulfonation. For example, alkylation of Intermediate 2bb with an alkylhalide in the presence of a base, e.g., sodium hydride (NaH), andoptionally at elevated temperatures provides Intermediate 2cc. Treatmentof Intermediate 2cc with hydroxylamine and a base, e.g., aqueous sodiumhydroxide (aq. NaOH), in a solvent, e.g., tetrahydrofuran (THF) and/ormethanol (MeOH), provides compounds of Formula (I).

Methods of Using the Disclosed Compounds

Another aspect of the disclosure relates to a method of treating adisease associated with HDAC, e.g., HDAC6, modulation in a subject inneed thereof. The method involves administering to a patient in need oftreatment for diseases or disorders associated with HDAC, e.g., HDAC6,modulation an effective amount of a compound of Formula I. In anembodiment, the disease can be, but is not limited to, cancer,neurodegenerative disease, neurodevelopmental disease, inflammatory orautoimmune disease, infection, metabolic disease, hematologic disease,or cardiovascular disease.

Another aspect of the disclosure is directed to a method of inhibitingan HDAC, e.g., HDAC6. The method involves administering to a patient inneed thereof an effective amount of Formula I.

The present disclosure relates to compositions capable of modulating theactivity of (e.g., inhibiting) HDACs, for instance HDAC6. The presentdisclosure also relates to the therapeutic use of such compounds.

One therapeutic use of the compounds of the present disclosure is totreat proliferative diseases or disorders such as cancer. Cancer can beunderstood as abnormal or unregulated cell growth within a patient andcan include but is not limited to lung cancer, ovarian cancer, breastcancer, prostate cancer, pancreatic cancer, hepatocellular cancer, renalcancer and leukemias such as acute myeloid leukemia and acutelymphoblastic leukemia. Additional cancer types include T-cell lymphoma(e.g., cutaneous T-cell lymphoma, peripheral T-cell lymphoma), andmultiple myeloma.

One therapeutic use of the compounds of the present disclosure is totreat neurological diseases or disorders or neurodegeneration.Neurological disorders are understood as disorders of the nervous system(e.g., the brain and spinal cord). Neurological disorders orneurodegenerative diseases can include but are not limited to epilepsy,attention deficit disorder (ADD), Alzheimer's disease, Parkinson'sDisease, Huntington's Disease, amyotrophic lateral sclerosis, spinalmuscular atrophy, essential tremor, central nervous system trauma causedby tissue injury, oxidative stress-induced neuronal or axomaldegeneration, and multiple sclerosis.

Another therapeutic use of the compounds of the present disclosure is totreat neurodevelopmental disorders. Neurodevelopmental disorders caninclude, but are not limited to, Rett syndrome.

Another therapeutic use of the compounds of the present disclosure isalso to treat inflammatory diseases or disorders. Inflammation can beunderstood as a host's response to an initial injury or infection.Symptoms of inflammation can include but are not limited to redness,swelling, pain, heat and loss of function. Inflammation may be caused bythe upregulation of pro-inflammatory cytokines such as IL-1β, andincreased expression of the FOXP3 transcription factor.

Another therapeutic use of the compounds of the present disclosure isalso to treat autoimmune diseases or disorders. Autoimmune disorders areunderstood as disorders wherein a host's own immune system responds totissues and substances occurring naturally in the host's body.Autoimmune diseases can include but are not limited to Rheumatoidarthritis, spondylitis arthritis, psoriatic arthritis, multiplesclerosis, systemic lupus erythematosus, inflammatory bowel disease,graft versus host disease, transplant rejection, fibrotic disease,Crohn's Disease, type-1 diabetes, Eczema, and psoriasis.

Another therapeutic use of the compounds of the present disclosure isalso to treat infectious diseases or disorders. Infections or infectiousdiseases are caused by the invasion of a foreign pathogen. The infectionmay be caused by, for instance, a bacteria, a fungus, or virus. Forexample, a bacterial infection may be caused by a E. coli.

Yet another therapeutic use of the compounds of the present disclosureis also to treat metabolic diseases or disorders. Metabolic diseases canbe characterized as abnormalities in the way that a subject storesenergy. Metabolic disorders can include but are not limited to metabolicsyndrome, diabetes, obesity, high blood pressure, and heart failure.

Yet another therapeutic use of the compounds of the present disclosureis also to treat hematologic disorders. Hematologic diseases primarilyaffect the blood. Hematologic disorders can include but are not limitedto anemia, lymphoma, and leukemia.

Yet another therapeutic use of the compounds of the present disclosureis also to treat cardiovascular diseases or disorders. Cardiovasculardiseases affect the heart and blood vessels of a patient. Exemplaryconditions include but are not limited to cardiovascular stress,pressure overload, chronic ischemia, infarction-reperfusion injury,hypertension, atherosclerosis, peripheral artery disease, and heartfailure.

Another aspect of the present disclosure relates to a compound ofFormula (I), or a pharmaceutically acceptable salt, hydrate, solvate,prodrug, stereoisomer, or tautomer thereof, for use in treating orpreventing a disease associated with HDAC6 modulation. In someembodiments, the disease is cancer, neurodegenerative disease,neurodevelopmental disorder, inflammatory or autoimmune disease,infection, metabolic disease, hematologic disease, or cardiovasculardisease. In some embodiments, the compound inhibits a histonedeacetylase. In another embodiment, the compound inhibits azinc-dependent histone deacetylase. In another embodiment, the compoundinhibits the HDAC6 isozyme zinc-dependent histone deacetylase.

In another aspect, the present disclosure relates to the use of acompound of Formula (I), or a pharmaceutically acceptable salt, hydrate,solvate, prodrug, stereoisomer, or tautomer thereof, in the manufactureof a medicament for treating or preventing a disease associated withHDAC6 modulation. In some embodiments, the disease is cancer,neurodegenerative disease, neurodevelopmental disorder, inflammatory orautoimmune disease, infection, metabolic disease, hematologic disease,or cardiovascular disease. In some embodiments, the compound inhibits ahistone deacetylase. In another embodiment, the compound inhibits azinc-dependent histone deacetylase. In another embodiment, the compoundinhibits the HDAC6 isozyme zinc-dependent histone deacetylase.

In some embodiments, the cancer is cutaneous T-cell lymphoma, peripheralT-cell lymphoma, multiple myeloma, leukemia, lung, ovarian, breast,prostate, pancreatic, hepatocellular or renal cancer. In otherembodiments, the neurodegenerative disease is Alzheimer's, Huntington's,Parkinson's, Amyotrophic Lateral Sclerosis, or spinal muscular atrophy.In other embodiments, the neurodevelopmental disorder is Rett syndrome.In yet other embodiments, the inflammatory or autoimmune disease isrheumatoid arthritis, spondylitis arthritis, psoriatic arthritis,psoriasis, multiple sclerosis, systemic lupus erythematosus,inflammatory bowel diseases, graft versus host disease, transplantrejection or fibrotic disease.

The disclosed compound can be administered in effective amounts to treator prevent a disorder and/or prevent the development thereof insubjects.

Administration of the disclosed compounds can be accomplished via anymode of administration for therapeutic agents. These modes includesystemic or local administration such as oral, nasal, parenteral,transdermal, subcutaneous, vaginal, buccal, rectal or topicaladministration modes.

Depending on the intended mode of administration, the disclosedcompositions can be in solid, semi-solid or liquid dosage form, such as,for example, injectables, tablets, suppositories, pills, time-releasecapsules, elixirs, tinctures, emulsions, syrups, powders, liquids,suspensions, or the like, sometimes in unit dosages and consistent withconventional pharmaceutical practices. Likewise, they can also beadministered in intravenous (both bolus and infusion), intraperitoneal,subcutaneous or intramuscular form, all using forms well known to thoseskilled in the pharmaceutical arts.

Illustrative pharmaceutical compositions are tablets and gelatincapsules comprising a Compound of the Disclosure and a pharmaceuticallyacceptable carrier, such as a) a diluent, e.g., purified water,triglyceride oils, such as hydrogenated or partially hydrogenatedvegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil,safflower oil, fish oils, such as EPA or DHA, or their esters ortriglycerides or mixtures thereof, omega-3 fatty acids or derivativesthereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose,sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica,talcum, stearic acid, its magnesium or calcium salt, sodium oleate,sodium stearate, magnesium stearate, sodium benzoate, sodium acetate,sodium chloride and/or polyethylene glycol; for tablets also; c) abinder, e.g., magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesiumcarbonate, natural sugars such as glucose or beta-lactose, cornsweeteners, natural and synthetic gums such as acacia, tragacanth orsodium alginate, waxes and/or polyvinylpyrrolidone, if desired; d) adisintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthangum, algiic acid or its sodium salt, or effervescent mixtures; e)absorbent, colorant, flavorant and sweetener; f) an emulsifier ordispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909,labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex355, gelucire, vitamin E TGPS or other acceptable emulsifier; and/or g)an agent that enhances absorption of the compound such as cyclodextrin,hydroxypropyl-cyclodextrin, PEG400, PEG200.

Liquid, particularly injectable, compositions can, for example, beprepared by dissolution, dispersion, etc. For example, the disclosedcompound is dissolved in or mixed with a pharmaceutically acceptablesolvent such as, for example, water, saline, aqueous dextrose, glycerol,ethanol, and the like, to thereby form an injectable isotonic solutionor suspension. Proteins such as albumin, chylomicron particles, or serumproteins can be used to solubilize the disclosed compounds.

The disclosed compounds can be also formulated as a suppository that canbe prepared from fatty emulsions or suspensions; using polyalkyleneglycols such as propylene glycol, as the carrier.

The disclosed compounds can also be administered in the form of liposomedelivery systems, such as small unilamellar vesicles, large unilamellarvesicles and multilamellar vesicles. Liposomes can be formed from avariety of phospholipids, containing cholesterol, stearylamine orphosphatidylcholines. In some embodiments, a film of lipid components ishydrated with an aqueous solution of drug to a form lipid layerencapsulating the drug, as described in U.S. Pat. No. 5,262,564.

Disclosed compounds can also be delivered by the use of monoclonalantibodies as individual carriers to which the disclosed compounds arecoupled. The disclosed compounds can also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspanamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the disclosedcompounds can be coupled to a class of biodegradable polymers useful inachieving controlled release of a drug, for example, polylactic acid,polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters,polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked oramphipathic block copolymers of hydrogels. In one embodiment, disclosedcompounds are not covalently bound to a polymer, e.g., a polycarboxylicacid polymer, or a polyacrylate.

Parental injectable administration is generally used for subcutaneous,intramuscular or intravenous injections and infusions. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions or solid forms suitable for dissolving in liquid prior toinjection.

Another aspect of the disclosure relates to a pharmaceutical compositioncomprising a compound of Formula I and a pharmaceutically acceptablecarrier. The pharmaceutically acceptable carrier can further include anexcipient, diluent, or surfactant.

Compositions can be prepared according to conventional mixing,granulating or coating methods, respectively, and the presentpharmaceutical compositions can contain from about 0.1% to about 99%,from about 5% to about 90%, or from about 1% to about 20% of thedisclosed compound by weight or volume.

The dosage regimen utilizing the disclosed compound is selected inaccordance with a variety of factors including type, species, age,weight, sex and medical condition of the patient; the severity of thecondition to be treated; the route of administration; the renal orhepatic function of the patient; and the particular disclosed compoundemployed. A physician or veterinarian of ordinary skill in the art canreadily determine and prescribe the effective amount of the drugrequired to prevent, counter or arrest the progress of the condition.

Effective dosage amounts of the disclosed compounds, when used for theindicated effects, range from about 0.5 mg to about 5000 mg of thedisclosed compound as needed to treat the condition. Compositions for invivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150,250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosedcompound, or, in a range of from one amount to another amount in thelist of doses. In one embodiment, the compositions are in the form of atablet that can be scored.

Without wishing to be bound by any particular theory, the compounds ofthe present disclosure can inhibit HDACs such as HDAC6 by interactingwith the zinc (Zn²⁺) ion in the protein's active site via the hydroxamicacid group bound to the aromatic ring of the compound. The binding canprevent the zinc ion from interacting with its natural substrates, thusinhibiting the enzyme.

EXAMPLES

The disclosure is further illustrated by the following examples andsynthesis examples, which are not to be construed as limiting thisdisclosure in scope or spirit to the specific procedures hereindescribed. It is to be understood that the examples are provided toillustrate certain embodiments and that no limitation to the scope ofthe disclosure is intended thereby. It is to be further understood thatresort may be had to various other embodiments, modifications, andequivalents thereof which may suggest themselves to those skilled in theart without departing from the spirit of the present disclosure and/orscope of the appended claims.

The present disclosure includes a number of unique features andadvantages compared with other inhibitors of HDAC enzymes, for instanceHDAC6. For instance, the present disclosure features a unique class ofsmall molecule therapeutic agents of Formula I. The compounds weredesigned by using crystal structure information of HDAC ligand-proteincomplexes as well as advanced computational chemistry tools. Thesetechniques led to the development of new chemical scaffolds that wereiteratively refined to optimize key recognition features between theligand and receptor known to be necessary for potency.

Definitions used in the following examples and elsewhere herein are:

-   BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene-   Boc: t-butoxycarbonyl-   CCl₄: carbon tetrachloride-   CDCl₃: deuterated chloroform-   CH₂Cl₂: methylene chloride, dichloromethane-   CO (g): carbon monoxide gas-   Cs₂CO₃: cesium carbonate-   Cu(OAc)₂ copper (II) acetate-   CuI: copper (I) iodide-   DEAD: diethyl azodicarboxylate-   DIEA: diisopropylethylamine-   DMA: dimethylacetamide-   DMF: N,N-dimethylformamide-   DMSO: dimethylsulfoxide-   Et₃N: triethylamine-   Et₂O: diethyl ether-   EtOAc: EtOAc-   h: hours-   H₂O: water-   HCl: hydrochloric acid-   H₄NHCO₃: ammonium bicarbonate-   Johnphos: (2-biphenyl)di-tert-butylphosphine-   K₂CO₃: potassium carbonate-   KH₂PO₄ potassium dihydrogen phosphate-   MeCN: acetonitrile-   MeOH: methanol-   MgSO₄: magnesium sulfate-   NaBH(OAc)₃: sodium triacetoxyborohydride-   min: minutes-   Na(CN)BH₃: sodium cyanoborohydride-   Na₂SO₄: sodium sulfate-   NaHCO₃: sodium bicarbonate-   NaOH: sodium hydroxide-   NBS: N-bromosuccinimide-   NH₂OH: hydroxylamine-   NH₄Cl: ammonium chloride-   NH₄HCO₃: ammonium bicarbonate-   Pd(dppf)Cl₂:    [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-   Pd(dppf)Cl₂.CH₂Cl₂:    [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane    adduct-   Pd(OAc)₂: palladium(II) acetate-   Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0)-   Pd₂(dba)₃.CHCl₃ tris(dibenzylideneacetone)dipalladium(0)-chloroform    adduct-   pet. ether: petroleum ether-   prep-HPLC: preparatory high pressure liquid chromatography-   prep-TLC: preparatory thin layer chromatography-   RuPhos 2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl-   RuPhos-Pd-G2    chloro(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)-   TFA: trifluoroacetic acid-   THF: tetrahydrofuran-   Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene-   XPhos-Pd-G3    (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)    methanesulfonate

Example 1—Preparation of4-(benzo[d]oxazol-2-yl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl 3-bromo-4-(bromomethyl)benzoate

Methyl 3-bromo-4-methylbenzoate (25 g, 109.14 mmol, 1 equiv), NBS (21.5g, 120.80 mmol, 1.11 equiv), benzoyl peroxide (146 mg, 0.57 mmol, 0.01equiv), and CCl₄ (120 mL) were placed in a 250-mL round-bottom flask.The resulting solution was stirred overnight at 85° C. in an oil bath.The resulting mixture was cooled and concentrated under vacuum. Theresidue was purified by silica gel chromatography (EtOAc/pet. ether,1:10) to afford the title compound as a white solid (20 g) and usedwithout further purification.

Step-2: Methyl 3-bromo-4-((2-hydroxyethylamino)methyl)benzoate

Methyl 3-bromo-4-(bromomethyl)benzoate (20 g, 64.94 mmol, 1 equiv),K₂CO₃ (26.9 g, 194.63 mmol, 3 equiv), MeCN (100 mL), and2-aminoethan-1-ol (4.76 g, 77.93 mmol, 1.20 equiv) were placed in a250-mL round-bottom flask. The resulting solution was stirred for 2 h at−5° C. The resulting mixture was concentrated under vacuum, washed withwater (50 mL) and EtOAc (50 mL). The organic layer was concentratedunder vacuum and were placed in a 250-mL round-bottom flask.(MeOH/CH₂Cl₂, 1:20) to afford the title compound as a light yellow oil(16 g, 56% yield over 2 steps). MS: (ES, m/z): 288 [M+H]⁺.

Step-3: Methyl 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Methyl 3-bromo-4-((2-hydroxyethylamino)methyl)benzoate (7 g, 24.29 mmol,1 equiv), K₂CO₃ (6.6 g, 47.75 mmol, 1.97 equiv), CuI (912 mg, 4.79 mmol,0.20 equiv), and isopropanol (100 mL) were placed in a 250-mLround-bottom flask. The resulting solution was stirred overnight at 110°C. in an oil bath. The solution was cooled and the solids were filteredout. The filtrate was concentrated under vacuum and purified by silicagel chromatography (EtOAc/pet. ether, 1:1) to afford the title compoundas a yellow oil (3 g, 60% yield). ¹H-NMR (300 MHz, CDCl₃) δ(ppm):7.70-7.68 (t, 2H), 7.26-7.22 (t, 1H), 4.13-4.09 (t, 2H), 4.05 (s, 2H),3.93 (s, 3H), 3.50 (s, 1H), 3.30-3.28 (t, 2H). MS: (ES, m/z): 208[M+H]⁺.

Step-4: Methyl4-(benzo[d]oxazol-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed methyl2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (200 mg, 0.97mmol, 1 equiv), 2-bromo-1H-1,3-benzoxazole (285 mg, 1.45 mmol, 1.5equiv), CuI (37 mg, 0.19 mmol, 0.2 equiv), ethane-1,2-diol (0.1 mL) andphosphoperoxol potassium (263 mg, 1.95 mmol, 2 equiv). The resultingsolution was stirred overnight at 110° C. in an oil bath. The resultingmixture was cooled and concentrated under vacuum. The residue waspurified by silica gel chromatography (EtOAc/pet. ether, 1:5) to affordthe title compound as a yellow oil (197 mg, 63% yield). MS: (ES, m/z):325 [M+H]⁺.

Step-5:4-(Benzo[d]oxazol-2-yl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 100-mL round-bottom flask, was placed methyl4-(benzo[d]oxazol-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(100 mg, 0.31 mmol, 1 equiv), NH₂OH (50% in water, 1 mL), aq. 1N NaOH(0.62 mL, 2 equiv), and THF (3 mL). The resulting solution was stirredovernight at 40° C. in an oil bath. The crude product (80 mg) waspurified by Prep-HPLC (Column: Sunfire Prep C18 OBD, 5 μm, 19×150 mm;Mobile Phase A: Water/0.05% Formic Acid; Mobile Phase B: MeCN; Flowrate: 25 mL/min; Gradient: 5% B to 50% B in 9 min; Detector: UV 254, 220nm) to afford the title compound as a pink solid (29 mg, 29% yield).¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.16 (s, 1H), 9.03 (s, 1H), 7.50-6.98(t, 7H), 4.84 (s, 2H), 4.26-4.24 (t, 2H), 4.08-4.06 (t, 2H). MS: (ES,m/z): 326 [M+H]⁺.

TABLE 1 The following compounds were prepared according to the method ofExample 1. Found Structure M + H ¹H-NMR (300 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 421 [M + H]⁺ 11.18 (s, 1H), 9.06 (s, 1H), 7.50-7.34 (m, 5H),7.06-7.03 (m, 2H), 4.55-4.47 (t, 1H), 4.35 (s, 1H), 4.02 (d, 1H,), 3.73(s, 1H), 1.79 (s, 1H), 1.16-1.47 (m, 3H), 1.23-1.10 (m, 2H), 0.98-0.78(m, 5H)

(ES, m/z): 342 [M + H]⁺ 10.98 (s, 1H), 9.04 (s, 1H), 7.75 (d, J = 7.8Hz, 1H), 7.52- 7.22 (m, 5H), 7.08-7.02 (m, 1H), 4.83 (s, 2H), 4.27-4.11(m, 4H)

(ES, m/z): 305 [M + H]⁺ 11.16 (s, 1H), 9.03 (s, 1H), 8.18 (s, 1H),7.39-7.20 (m, 3H), 3.99 (s, 2H), 3.75-3.73 (d, J = 8 Hz, 2H), 2.96 (s,2H), 2.20-2.18 (d, J = 5.6 Hz, 2H), 1.70-1.63 (m, 4H), 1.47-1.46 (d, J =8 Hz, 1H), 1.24-1.11 (m, 4H), 0.85-0.77 (m, 2H)

(ES, m/z): 423 [M + H]⁺ 11.25 (s, 1H), 9.06 (br s, 1H), 7.70-7.72(m,1H), 7.24- 7.51 (m, 6H), 4.88 (s, 2H), 4.50 (s, 2H), 4.08-4.10 (d, J =7.2 Hz, 2H), 3.91 (s, 2H), 3.53-3.59 (d, J = 24.4 Hz, 2H), 2.87-2.94(m,2H), 1.80-1.91 (m, 1H), 0.92 (s, 4H)

Example 2—Preparation ofN-hydroxy-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 50-mL round-bottom flask, was placed methyl2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (100 mg, 0.48mmol, 1 equiv), Pd₂(dba)₃ (50 mg, 0.05 mmol, 0.11 equiv), Xantphos (14mg, 0.02 mmol, 0.05 equiv), Cs₂CO₃ (326 mg, 1 mmol, 2.08 equiv), dioxane(10 mL) and bromobenzene (117 mg, 0.75 mmol, 1.54 equiv). The resultingmixture was stirred overnight at 100° C. in an oil bath. After cooling,the solids were filtered out and the filtrate was concentrated undervacuum. The residue was purified by prep-TLC (EtOAc/pet. ether, 1:5) toafford the title compound as a light yellow oil (50 mg, 37% yield). MS:(ES, m/z): 284 [M+H]⁺.

Step-2:N-Hydroxy-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 100-mL round-bottom flask, was placed methyl4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (50 mg,0.18 mmol, 1 equiv), NH₂OH (50% in water, 1 mL, 50 equiv), aq. 1N NaOH(0.36 mL, 2 equiv) and THF (3 mL). The resulting solution was stirredovernight at 40° C. in an oil bath. The crude product was purified byPrep-HPLC (Column: Sunfire Prep C18 ODB, 5 μm, 19×150 mm; Mobile PhaseA: Water/0.05% Formic Acid; Mobile Phase B: MeCN; Flow rate: 25 mL/min;Gradient: 5% B to 55% B in 8 min; Detector: UV 254, 220 nm) to affordthe title compound as a pink oil (2.5 mg, 5% yield). ¹H-NMR (400 MHz,DMSO-d₆) δ(ppm): 11.12 (s, 1H), 9.03 (s, 1H), 7.56-6.56 (m, 8H), 4.66(s, 2H), 4.17-4.10 (t, 2H), 3.91-3.80 (t, 2H). MS: (ES, m/z): 326[M+H]⁺.

TABLE 2 The following compounds were prepared according to the method ofExample 2. Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 378 [M + H]⁺ 11.15 (s, 1H), 9.02 (s, 1H), 7.79-7.76 (t, 1H),7.60-7.58 (t, 1H), 7.41-7.39 (t, 1H), 7.30-7.22 (t, 3H), 4.86 (s, 2H),4.20-4.19 (t, 2H), 4.06-4.05 (t, 2H)

(ES, m/z): 353 [M + H]⁺ 11.11 (s, 1H), 9.04 (s, 1H), 7.59-7.57 (t, 1H),7.50-7.43 (t, 1H), 7.30-7.28 (t, 2H), 7.09-7.08 (t, 1H), 6.90-6.87 (t,1H), 4.69 (s, 2H), 4.13-4.11 (t, 2H), 3.90-3.88 (t, 2H)

(ES, m/z): 286 [M + H]⁺ 11.06 (s, 1H), 9.03 (s, 1H), 8.04-8.05 (t, J =1.5 Hz, 1H), 7.29-7.49 (m, 4H), 6.86-6.89 (d, J = 8.7 Hz, 1H), 6.53-6.57 (m, 1H), 4.77 (s, 2H), 4.10 (s, 4H)

Example 3—Preparation ofN-hydroxy-4-(pyridin-3-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl4-(pyridin-3-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 25-mL sealed tube, was placed a solution of methyl2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (200 mg, 0.97mmol, 1 equiv) in 1,4-dioxane (10 mL), 3-bromopyridine (171 mg, 1.08mmol, 1.5 equiv), Pd₂(dba)₃.CHCl₃ (15 mg, 0.02 equiv), BINAP (20 mg,0.03 mmol, 0.03 equiv) and Cs₂CO₃ (489 mg, 1.50 mmol, 2 equiv). Theresulting mixture was stirred for 1.5 h at 150° C. in a microwavereactor. The reaction mixture was concentrated under vacuum. The residuewas diluted with H₂O (30 mL) and then extracted with EtOAc (3×100 mL).The organic layer was concentrated and the residue was purified bysilica gel chromatography (MeOH/CH₂Cl₂, 1:10) to afford the titlecompound as a light yellow oil (50 mg, 18% yield). MS: (ES, m/z): 285[M+H]⁺.

Step-2:N-Hydroxy-4-(pyridin-3-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 100-mL round-bottom flask, was placed a solution of methyl4-(pyridin-3-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(50 mg, 0.18 mmol, 1 equiv) in THF/MeOH (4:1, 2.5 mL), NH₂OH (50% inwater, 1 mL, 60 equiv), aq. 1N NaOH (0.5 mL, 2 equiv). The resultingsolution was stirred overnight at room temperature. The mixture waspurified by Prep-HPLC (Column: HSS C18 OBD, 1.8 μm, 2.1×50 mm; MobilePhase A: Water/0.05% TFA; Mobile Phase B: MeCN/0.05% TFA; Flow rate: 0.7mL/min; Gradient: 5% B to 95% B in 2 min, hold 0.6 min; Detector: UV 254nm) to afford the title compound as a yellow solid (3.3 mg, 6% yield).¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 8.33 (b, 1H), 8.26 (s, 1H), 7.83 (b,1H), 7.62 (s, 1H), 7.39-7.09 (m, 4H), 4.72 (s, 1H), 4.13 (b, 2H), 3.93(s, 2H). MS: (ES, m/z): 286 [M+H]⁺.

TABLE 3 The following compound was prepared according to the method ofExample 3. Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 286 [M + H]⁺ 8.30-8.08 (m, 3H), 7.58-7.30 (m, 3H), 6.81 (s,2H), 4.70 (s, 2H), 4.13 (s, 2H), 3.92 (s, 2H)

Example 4: Preparation ofN-hydroxy-4-(p-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl4-(p-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 100-mL round-bottom flask, was placed methyl2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (200 mg, 0.97mmol, 1 equiv), p-tolylboronic acid (162 mg, 1.19 mmol, 1.24 equiv),Cu(OAc)₂ (18 mg, 0.10 mmol, 0.1 equiv), pyridine (16 mg, 0.20 mmol, 0.21equiv), CH₂Cl₂ (10 mL). The resulting solution was stirred for 2 h atroom temperature, then concentrated under vacuum. The residue waspurified by silica gel chromatography (EtOAc/pet. ether, 1:5) to affordthe title compound as a light yellow solid (120 mg, 42% yield). MS: (ES,m/z): 298 [M+H]⁺.

Step-2:N-Hydroxy-4-(p-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 100-mL round-bottom flask was placed methyl4-(p-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (120mg, 0.40 mmol, 1 equiv), NH₂OH (50% in water, 1 mL, 38 equiv), aq. 1NNaOH (1 mL, 2.5 equiv), and THF/MeOH (4:1, 3 mL). The resulting solutionwas stirred overnight at 40° C. in an oil bath. The mixture was purifiedby Prep-HPLC (Column: Sunfire Prep C18 OBD, 5 μm, 19×150 mm; MobilePhase A: Water/0.05% Formic Acid; Mobile Phase B: MeCN; Flow rate: 25mL/min; Gradient: 5% B to 60% B in 10 min; Detector: UV 254, 220 nm) toafford the title compound as a pink solid (31 mg, 26% yield). ¹H-NMR(400 MHz, DMSO-d₆) δ(ppm): 11.11 (s, 1H), 9 (s, 1H), 7.55-7.52 (t, 1H),7.37-7.34 (t, 1H), 7.27-7.27 (t, 1H), 6.93-6.90 (t, 2H), 6.78-6.79 (t,2H), 4.62 (s, 2H), 4.11-4.09 (t, 2H), 3.85-3.83 (t, 2H), 2.11 (s, 3H).MS: (ES, m/z): 299 [M+H]⁺.

Example 5—Preparation ofN-hydroxy-4-(piperidine-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl4-(piperidine-1-carbonyl)-2,3,4,5-tetrahydrobenzo[^(f)][1,4]oxazepine-8-carboxylate

Into a 10-mL round-bottom flask, was placed a solution of methyl2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (104 mg, 0.50mmol, 1 equiv) in CH₂Cl₂ (2 mL), Et₃N (101.5 mg, 1 mmol, 2 equiv) andpiperidine-1-carbonyl chloride (82 mg, 0.56 mmol, 1.1 equiv). Theresulting solution was stirred overnight at room temperature. Thereaction was then quenched by the addition of water (20 mL) andextracted with CH₂Cl₂ (3×20 mL). The combined organic layers were washedwith brine (30 mL), dried over anhydrous Na₂SO₄, filtered, andconcentrated under vacuum. The residue was purified by silica gelchromatography (EtOAc/pet. ether, 1:3) to afford the title compound as awhite solid (133 mg, 83% yield). MS: (ES, m/z): 319 [M+H]⁺.

Step-2:N-Hydroxy-4-(piperidine-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 25-mL round-bottom flask, was placed a solution of methyl4-(piperidine-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(133 mg, 0.42 mmol, 1 equiv) in THF/MeOH (4:1, 2 mL), aq. 1N NaOH (0.836mL, 2 equiv) and NH₂OH (50% in water, 828 mg, 25 mmol, 30 equiv). Theresulting solution was stirred for 2 h at room temperature. The pH valueof the solution was adjusted to 6 with 2N HCl. The crude product waspurified by Prep-HPLC (Column: HSS C18 OBD, 1.8 μm, 2.1×50 mm; MobilePhase A: Water/0.05% TFA; Mobile Phase B: MeCN/0.05% TFA; Flow rate: 0.7mL/min; Gradient: 5% B to 95% B in 2 min, hold 0.6 min; Detector: UV254, 220 nm) to afford the title compound as a pink solid (49 mg, 27%yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.18 (s, 1H), 7.36-7.39 (m,1H), 7.28-7.31 (t, J=1.6 Hz, 2H), 4.37 (s, 2H), 4.17-4.20 (t, J=4.4 Hz,2H), 3.55-3.57 (t, J=4.8 Hz, 2H), 3.06-3.07 (d, J=5.2 Hz, 2H), 1.49-1.51(d, J=6 Hz, 6H). MS: (ES, m/z): 320 [M+H]⁺.

TABLE 4 The following compounds were prepared according to the method ofExample 5. Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 359 [M + H]⁺ 11.20 (s, 1H), 7.30-7.46 (m, 3H), 6.99-7.01 (d,J = 8.8 Hz, 1H), 6.87-6.89 (t, J = 2.4 Hz, 3H), 4.72 (s, 1H), 4.61 (s,1H), 4.25 (s, 1H), 4.16 (s, 1H), 3.98 (s, 1H), 3.83 (s, 1H), 3.72 (s,3H)

(ES, m/z): 335 [M + H]⁺ 11.17 (s, 1H), 7.40-7.42 (d, J = 7.2 Hz, 1H),7.28-7.33 (t, J = 8 Hz, 2H), 4.51 (s, 3H), 4.07 (s, 2H), 3.76 (s, 2H),1.59-1.67 (m, 4H), 1.28-281.42 (m, 6H)

(ES, m/z): 356 [M + H]⁺ 11.22 (s, 1H), 9.02-9.06 (br s, 1H), 7.31-7.42(m, 3H), 4.47 (s, 2H), 4.14-4.17 (m, 2H), 3.64-3.66 (m, 2H), 3.01-3.02(m, 4H), 1.44 (m, 6H)

Example 6—Preparation ofN8-hydroxy-N4-methyl-N4-phenyl-2,3,7,8-tetrahydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide

Step-1: Methyl4-(methyl(phenyl)carbamoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 25-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of N-methylaniline (26 mg,0.24 mmol, 1 equiv) in CH₂Cl₂ (5 mL). This was followed by the additionof ditrichloromethyl carbonate (25 mg, 0.08 mmol, 0.35 equiv) dropwisewith stirring. Et₃N (61 mg, 0.60 mmol, 2.5 equiv) was added and theresulting mixture was stirred for 10 minutes at room temperature. Methyl2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (50 mg, 0.24mmol, 1 equiv) was added and the resulting solution was stirred for anadditional 30 min at room temperature. The reaction was then quenched bythe addition of sat. aq. NaHCO₃ solution (10 mL). The crude residue waspurified by Prep-TLC to afford the title compound as a light yellowsolid (25 mg, 30% yield). MS: (ES, m/z): 340 [M+H]⁺.

Step-2:N8-Hydroxy-N4-methyl-N4-phenyl-2,3,7,8-tetrahydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide

Into a 25-mL round-bottom flask was placed a solution of methyl4-(methyl(phenyl)carbamoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(65 mg, 0.19 mmol, 1 equiv) in THF/MeOH (4:1, 2 mL). This was followedby the addition of NH₂OH (50% in water, 0.35 mL, 30 equiv) dropwise withstirring. To this was added aq. 1N NaOH (0.57 mL, 3 equiv). Theresulting solution was stirred for 30 min at room temperature. The pHvalue of the solution was adjusted to 5-6 with 1N HCl. The crude productwas purified by Prep-HPLC (Column: XBridge RP C18 OBD, 5 μm, 19×150 mm;Mobile Phase A: Water/0.05% TFA; Mobile Phase B: MeCN; Flow rate: 25mL/min; Gradient: 5% B to 44% B in 7 min; Detector: UV 254 nm) to affordthe title compound as a pink solid (61 mg, 94% yield). ¹H-NMR (400 MHz,DMSO-d₆) δ(ppm): 11.16 (s, 1H), 7.23-7.33 (m, 3H), 7.14 (s, 1H),7.01-7.09 (m, 3H), 6.99 (d, 1H), 4.35 (s, 2H), 4.04-4.07 (s, 2H),3.40-3.43 (s, 2H), 3.03 (s, 3H). MS: (ES, m/z): 341 [M+H]⁺.

Example 7—Preparation of4-cyclohexyl-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl4-cyclohexyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 25-mL round-bottom flask, was placed methyl2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (206 mg, 0.99mmol, 1 equiv), CH₂Cl₂ (8 mL) and cyclohexanone (106 mg, 1.08 mmol, 1.1equiv). The solution was stirred for 1 h at room temperature. Then tothis was added NaBH(OAc)₃ (2.15 g, 10.14 mmol, 10 equiv). The resultingsolution was stirred for 4 h at room temperature. The reaction mixturewas cooled to 0° C. with a water/ice bath. The reaction was thenquenched by the addition of water (20 mL) and extracted with CH₂Cl₂(3×50 mL). The organic phase was washed with sat. aq. NaHCO₃ solution(50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated undervacuum to afford the title compound as brown oil (80 mg) which was usedwithout further purification. MS: (ES, m/z): 289 [M+H]⁺.

Step-2:4-Cyclohexyl-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 25-mL round-bottom flask, was placed a solution of methyl4-cyclohexyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (140mg, 0.48 mmol, 1 equiv) in THF/MeOH (4:1, 2 mL), aq. 1N NaOH (0.969 mL,2 equiv) and NH₂OH (50% in water, 959 mg, 30 equiv). The resultingsolution was stirred for 2 h at room temperature. The pH value of thesolution was adjusted to 6 with 2N HCl. The crude product was purifiedby Prep-HPLC (Column: HSS C18 OBD, 1.8 μm, 2.1×50 mm; Mobile Phase A:Water/0.05% TFA; Mobile Phase B: MeCN/0.05% TFA; Flow rate: 0.7 mL/min;Gradient: 5% B to 95% B in 2 min, hold 0.6 min; Detector: UV 254, 220nm) to afford the title compound as an orange solid (35 mg, 18% yield).¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.33 (s, 1H), 9.98 (s, 1H), 9.15 (s,1H), 7.54 (s, 2H), 7.44 (s, 1H), 4.49-4.64 (m, 2H), 4.09-4.14 (t, J=12.8Hz, 1H), 3.65-3.70 (d, J=20.4 Hz, 2H), 3.39 (s, 1H), 2.02-2.12 (m, 2H),1.83-1.85 (d, J=11.6 Hz, 2H), 1.46-1.64 (m, 3H), 1.21-1.31 (m, 3H). MS:(ES, m/z): 290 [M+H]⁺.

TABLE 5 The following compounds were prepared according to the method ofExample 7. Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 280 [M + H]⁺ 11.21 (s, 1H), 10.10 (s, 1 H), 7.37-7.45 (m,3H), 4.05- 4.15 (d, J = 37.2 Hz, 2H), 3.94 (s, 2H), 3.21-3.24 (m, 2H),3.14 (s, 2H), 2.74-2.78 (m, 8H)

Example 8—Preparation ofN-hydroxy-4-(2-methoxyethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl4-(2-methoxyethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 10-mL round-bottom flask, was placed a solution of methyl2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (104 mg, 0.50mmol, 1 equiv) in DMF (2 mL), K₂CO₃ (138.1 mg, 1 mmol, 2 equiv) and1-iodo-2-methoxyethane (102.8 mg, 0.55 mmol, 1.1 equiv). The resultingsolution was stirred overnight at room temperature. The reaction wasthen quenched by the addition of water (20 mL) and extracted with CH₂Cl₂(3×20 mL). The combined organic layers were washed with brine (30 mL),dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum.The residue was purified by silica gel chromatography (MeOH/CH₂Cl₂,1:10) to afford the title compound as a yellow oil (46 mg). MS: (ES,m/z): 266 [M+H]⁺.

Step-2:N-Hydroxy-4-(2-methoxyethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 25-mL round-bottom flask, was placed a solution of methyl4-(2-methoxyethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(46 mg, 0.17 mmol, 1 equiv) in THF/MeOH (4:1, 2 mL), aq. 1N NaOH (0.347mL, 2 equiv) and NH₂OH (50% in water, 343.7 mg, 10.42 mmol, 30 equiv).The resulting solution was stirred for 2 h at room temperature. The pHvalue of the solution was adjusted to 6 with 2N HCl. The crude productwas purified by Prep-HPLC (Column: HSS C18 OBD, 1.8 μm, 2.1×50 mm;Mobile Phase A: Water/0.05% TFA; Mobile Phase B: MeCN/0.05% TFA; Flowrate: 0.7 mL/min; Gradient: 5% B to 95% B in 2 min, hold 0.6 min;Detector: UV 254, 220 nm) to afford the title compound as an orangesolid (29 mg, 44% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.31 (s,1H), 10.29 (s, 1H), 9.15 (s, 1H), 7.50-7.55 (m, 2H), 7.44 (s, 1H),4.24-4.51 (m, 4H), 3.69 (s, 4H), 3.34 (s, 3H). MS: (ES, m/z): 267[M+H]⁺.

Example 9—Preparation ofN-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide2,2,2-trifluoroacetate

Into a 8-mL vial, was placed methyl2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (60 mg, 0.29mmol, 1 equiv) in THF/MeOH (4:1, 1.5 mL), aq. 1N NaOH (0.58 mL, 0.58mmol, 2 equiv) and NH₂OH (50% in water, 0.58 mL, 8.69 mmol, 30 equiv).The resulting solution was stirred for 2 h at room temperature. Thecrude product was purified by Prep-HPLC (Column: XBridge RP C18 OBD, 5μm, 19×150 mm; Mobile Phase A: Water/0.05% TFA; Mobile Phase B: MeCN;Flow rate: 25 mL/min; Gradient: 4% B to 58% B in 7 min; Detector: UV254, 220 nm) to afford the title compound as a pink solid (21 mg, 23%yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.29 (s, 1H), 9.42 (br s,2H), 9.11 (s, 1H), 7.48-7.52 (m, 2H), 7.42-7.45 (s, 1H), 4.37 (s, 2H),4.21-4.23 (m, 2H), 3.49-3.51 (m, 2H). MS: (ES, m/z): 209 [M+H]⁺.

Example 10—Preparation ofN-hydroxy-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide2,2,2-trifluoroacetate

Step-1: Methyl4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 25-mL round-bottom flask, was placed methyl2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (100 mg, 0.31mmol, 1 equiv), acetic acid (3 mL) and paraformaldehyde (28 mg, 0.93mmol, 3 equiv). The resulting mixture was stirred for 2 h at roomtemperature. Then acetyl ethaneperoxoate sodioboranyl acetate (327 mg,1.54 mmol, 5 equiv) was added and the reaction was stirred for anadditional 18 h at room temperature. The resulting mixture wasconcentrated under vacuum, diluted with EtOAc (50 mL), washed with H₂O(3×25 mL), dried over anhydrous MgSO₄, filtered and concentrated toafford the title compound as a yellow solid (100 mg) which was usedwithout further purification. MS: (ES, m/z): 222 [M+H]⁺.

Step-2:N-Hydroxy-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide2,2,2-trifluoroacetate

Into a 8-mL vial, was placed methyl4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (100 mg,0.45 mmol, 1 equiv) in THF/MeOH (4:1, 1 mL), aq. 1N NaOH (0.9 mL, 0.90mmol, 2 equiv) and NH₂OH (50% in water, 0.9 mL, 13.56 mmol, 30 equiv).The resulting solution was stirred for 1 h at room temperature. Thecrude product was purified by Prep-HPLC (Column: XBridge RP C18 OBD, 5μm, 19×150 mm; Mobile Phase A: Water/0.05% TFA; Mobile Phase B: MeCN;Flow rate: 25 mL/min; Gradient: 4% B to 58% B in 7 min; Detector: UV254, 220 nm) to afford the title compound as a yellow oil (45 mg, 29%yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.31 (s, 1H), 10.54 (s, 1H),9.91 (s, 1H), 7.42-7.54 (m, 3H), 4.48 (s, 1H), 4.26 (s, 2H), 3.62 (s,2H), 3.88 (s, 3H). MS: (ES, m/z): 223 [M+H]⁺.

Example 11—Preparation of(R)—N-hydroxy-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl (R)-3-bromo-4-(((2-hydroxypropyl)amino)methyl)benzoate

Into a 250-mL round-bottom flask, was placed a solution of methyl3-bromo-4-(bromomethyl)benzoate (7 g, 22.73 mmol, 1 equiv) in MeCN (80mL), potassium carbonate (4.69 g, 33.93 mmol, 1.50 equiv) and(2R)-1-aminopropan-2-ol (1.7 g, 22.63 mmol, 1 equiv). The resultingmixture was stirred for 3 h at room temperature and then concentratedunder vacuum. The residue was diluted with EtOAc (80 mL) and theresulting solution was washed with water (3×30 mL). The organic phasewas concentrated under vacuum to afford the title compound as anoff-white solid (3 g) which was used without further purification. MS:(ES, m/z): 302 [M+H]⁺.

Step-2: Methyl(R)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of methyl(R)-3-bromo-4-(((2-hydroxypropyl)amino)methyl)benzoate (2.75 g, 9.10mmol, 1 equiv) in isopropanol (32 mL), potassium carbonate (2.53 g,18.31 mmol, 2 equiv) and CuI (520 mg, 2.73 mmol, 0.30 equiv). Theresulting solution was stirred for 21 h at 110° C. in an oil bath. Theresulting mixture was concentrated under vacuum and the residue wasdiluted with EtOAc (100 mL). The resulting mixture was washed with water(3×150 mL) and the organic phase was concentrated, then the residue waspurified by silica gel chromatography (CH₂Cl₂/MeOH, 99:1) to afford thetitle compound as a brown oil (1.1 g, 55% yield). MS: (ES, m/z): 222[M+H]⁺.

Step-3:(R)—N-Hydroxy-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed a solution of methyl(R)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (50mg, 0.23 mmol, 1 equiv) in THF/MeOH (4:1, 1 mL), NH₂OH (50% in water,0.44 mL, 30 equiv) and aq. 1N NaOH (0.45 mL, 2 equiv). The resultingsolution was stirred for 14 h at room temperature. The crude product waspurified by Prep-HPLC (Column: Sunfire Prep C18 OBD, 5 μm, 19×150 mm;Mobile Phase A: Water/0.05% TFA; Mobile Phase B: MeCN; Flow rate: 25mL/min; Gradient: 4% B to 18% B in 6 min; Detector: UV 254, 220 nm) toafford the title compound as a brown oil (15 mg, 21% yield). ¹H-NMR (400MHz, DMSO-d₆) δ(ppm): 11.28 (s, 1H), 9.24 (br s, 2H), 7.56-7.33 (m, 3H),4.45-4.38 (d, J=7.2 hz, 1H), 4.31-4.28 (d, J=7.2 hz, 1H), 4.18-4.11 (m,1H), 3.53-3.49 (d, J=6.4 Hz, 1H), 3.29-3.28 (m, 1H), 1.39-1.37 (m, 3H).MS: (ES, m/z): 223 [M+H]⁺.

Example 12—Preparation of(R)—N8-hydroxy-N4-(4-methoxyphenyl)-2-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide

Step-1: Methyl(R)-4-((4-methoxyphenyl)carbamoyl)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, were placed a solution of methyl(R)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (150mg, 0.68 mmol, 1 equiv) in CH₂Cl₂ (4 mL), Et₃N (81 mg, 0.80 mmol, 3equiv) and 1-isocyanato-4-methoxybenzene (167 mg, 1.12 mmol, 1.5 equiv).The resulting mixture was stirred for 16 h at room temperature and thenwashed with water (2×10 mL). The organic phase was concentrated and theresidue was purified by silica gel chromatography (EtOAc/pet. ether,1:3) to afford the title compound as a light yellow oil (40 mg, 16%yield). MS: (ES, m/z): 371 [M+H]⁺.

Step-2:(R)—N8-Hydroxy-N4-(4-methoxyphenyl)-2-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide

Into a 8-mL vial, was placed methyl(R)-4-((4-methoxyphenyl)carbamoyl)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(40 mg, 0.11 mmol, 1 equiv) in THF/MeOH (4:1, 2 mL). To this was addedaq. 1N NaOH (0.22 mL, 2 equiv) and NH₂OH (50% in water, 0.22 mL, 30equiv). The resulting solution was stirred for 3 h at room temperature.The crude product was purified by Prep-HPLC (Column: Column: XBridge XPC18 OBD, 5 μm, 19×150 mm; Mobile Phase A: Water/0.05% TFA; Mobile PhaseB: MeCN; Flow rate: 0.7 mL/min; Gradient: 5% B to 80% B in 7 min;Detector: UV 254, 220 nm) to afford the title compound as an off-whitesolid (21 mg, 52% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.14 (s,1H), 9 (br s, 1H), 8.35 (s, 1H), 7.42-7.39 (m, 2H), 7.37-7.33 (m, 1H),7.27-7.20 (m, 2H), 6.79-7.77 (m, 2H), 4.84-4.80 (d, J=15.6 Hz, 1H),4.42-4.39 (d, J=15.6 Hz, 1H), 4.03-4 (d, J=12.4 Hz, 2H), 3.67 (s, 3H),3.32-3.28 (m, 1H), 1.32-1.30 (d, J=6.0 Hz, 3H). MS: (ES, m/z): 372[M+H]⁺.

Example 13—Preparation of(R)—N-Hydroxy-4-(4-methoxyphenylsulfonyl)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(R)-4-((4-methoxyphenyl)sulfonyl)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 40-mL round-bottom flask, was placed a solution of methyl(R)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (100mg, 0.45 mmol, 1 equiv) in CH₂Cl₂ (20 mL), 4-methoxybenzene-1-sulfonylchloride (140 mg, 0.68 mmol, 1.5 equiv), Et₃N (140 mg, 1.38 mmol, 3equiv) and 4-dimethylaminopyridine (55 mg, 0.45 mmol, 1 equiv). Theresulting mixture was stirred for 10 h at room temperature. The abovemixture was concentrated under vacuum. The residue was purified bysilica gel chromatography (EtOAc/pet. ether, 1:1) to afford the titlecompound as a light yellow oil (80 mg, 45% yield). MS: (ES, m/z): 392[M+H]⁺.

Step-2:(R)—N-Hydroxy-4-((4-methoxyphenyl)sulfonyl)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 10-mL vial, was placed a solution of methyl(R)-4-((4-methoxyphenyl)sulfonyl)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(80 mg, 0.21 mmol, 1 equiv) in THF/MeOH (4:1, 2 mL). This was followedby the addition of aq. 1N NaOH (10.42 mL, 2 equiv) and NH₂OH (50% inwater, 0.42 mL, 30 equiv). The resulting solution was stirred for 2 h atroom temperature. The crude product was purified by Prep-HPLC (Column:XBridge XP C18 OBD, 5 μm, 19×150 mm; Mobile Phase A: Water/0.05% TFA;Mobile Phase B: MeCN; Flow rate: 0.7 mL/min; Gradient: 8% B to 45% B in7 min; Detector: UV 254 nm) to afford the title compound as a pink solid(78 mg, 97% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.17 (br s, 1H),7.69-7.68 (m, 2H), 7.42-7.40 (m, 1H), 7.33-7.31 (m, 1H), 7.25-7.24 (m,1H), 7.05-7.02 (m, 2H), 4.57-4.53 (m, 1H), 4.25-4.21 (m, 1H), 4.03-3.98(m, 1H), 3.81 (s, 3H), 3.68-3.65 (m, 1H), 3.24-3.18 (m, 1H), 1.26-1.24(d, J=6.4 Hz, 3H). MS: (ES, m/z): 393 [M+H]⁺.

Example 14—Preparation of(R)—N-hydroxy-4-(4-methoxybenzyl)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(R)-4-(4-methoxybenzyl)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 50-mL flask, was placed a solution of methyl(R)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (100mg, 0.45 mmol, 1 equiv) in THF (10 mL). This was followed by theaddition of sodium hydride (60%, 50 mg, 2.08 mmol, 3 equiv). To this wasadded 1-(bromomethyl)-4-methoxybenzene (90 mg, 0.45 mmol, 1 equiv). Theresulting mixture was stirred for 4 h at room temperature. The reactionwas then quenched by the addition of water (3 mL). The organic layer wasconcentrated under vacuum to afford the title compound as a light yellowoil (80 mg) which was used without further purification. MS: (ES, m/z):342 [M+H]⁺.

Step-2:(R)—N-Hydroxy-4-(4-methoxybenzyl)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 10-mL vial, was placed a solution of methyl(R)-4-(4-methoxybenzyl)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(70 mg, 0.21 mmol, 1 equiv) in THF/MeOH (4:1, 2 mL). To the abovemixture was added aq. 1N NaOH (0.42 mL, 2 equiv) and NH₂OH (50% inwater, 0.42 mL, 30 equiv). The resulting solution was stirred for 3 h atroom temperature. The crude product was purified by Prep-HPLC (Column:XBridge XP C18 OBD, 5 μm, 19×150 mm; Mobile Phase A: Water/0.05% TFA;Mobile Phase B: MeCN; Flow rate: 0.7 mL/min; Gradient: 7% B to 55% B in7 min; Detector: UV 254 nm) to afford the title compound as a pink solid(34 mg, 49% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.30 (br s, 1H),9.12 (br s, 1H), 7.53-7.44 (m, 5H), 7.03 (m, 2H), 4.49-3.97 (m, 5H),3.79 (s, 3H), 3.60-3.35 (m, 2H), 1.34-1.33 (d, J=5.2 Hz, 3H). MS: (ES,m/z): 343 [M+H]⁺.

Example 15—Preparation of(R)—N-hydroxy-2-methyl-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(R)-2-methyl-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial purged and maintained with nitrogen, placed a solutionof methyl(R)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (300mg, 1.36 mmol, 1 equiv) in dioxane (8 mL), iodobenzene (827 mg, 4.05mmol, 3 equiv), Xantphos (312 mg, 0.54 mmol, 0.4 equiv), Cs₂CO₃ (1.33 g,4.05 mmol, 3 equiv) and Pd(OAc)₂ (61 mg, 0.27 mmol, 0.2 equiv). Theresulting mixture was stirred for 20 h at 110° C. in an oil bath. Theresulting mixture was concentrated under vacuum. The residue was dilutedwith EtOAc (20 mL), washed with water (3×15 mL), dried and concentrated.The residue was purified by silica gel chromatography (EtOAc/pet. ether,1:3) to afford the title compound as a brown oil (270 mg, 67% yield).MS: (ES, m/z): 298 [M+H]⁺.

Step-2:(R)—N-hydroxy-2-methyl-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed methyl(R)-2-methyl-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(270 mg, 0.91 mmol, 1 equiv) in THF/MeOH (4:1, 3 mL). To the abovemixture was added aq. 1N NaOH (1.82 mL, 1.82 mmol, 2 equiv) and NH₂OH(50% in water, 1.83 mL, 27.18 mmol, 30 equiv). The resulting mixture wasstirred for 3 h at room temperature. The crude product was purified byPrep-HPLC (Column: XBridge XP C18 OBD, 5 μm, 19×150 mm; Mobile Phase A:Water/0.05% TFA; Mobile Phase B: MeCN; Flow rate: 0.7 mL/min; Gradient:5% B to 62% B in 7 min; Detector: UV 254 nm) to afford the titlecompound as a brown solid (134 mg, 49% yield). ¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 11.29 (br s, 1H), 7.55-7.52 (d, J=7.5 Hz, 1H), 7.37-7.28 (m,2H), 7.12-7.07 (m, 2H), 6.87-6.84 (m, 2H), 6.59-6.54 (m, 1H), 4.84-4.79(d, J=16.2 Hz, 1H), 4.48-4.36 (d, J=15.6 Hz, 1H), 4.07-3.87 (m, 3H),1.37-1.35 (d, J=6.3 Hz, 3H). MS: (ES, m/z): 299 [M+H]⁺.

Example 16—Preparation of(R)—N-hydroxy-2,4-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(R)-2,4-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, was placed a solution of methyl(2R)-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxylate (70 mg,0.32 mmol, 1 equiv) in acetic acid (1.5 mL). This was followed by theaddition of formaldehyde (40% in water, 28 mg, 0.93 mmol, 3 equiv) inportions. The mixture was stirred for 2 h at room temperature. To thiswas added NaBH(OAc)₃ (334 mg, 1.58 mmol, 5 equiv), in portions at 0° C.The resulting solution was stirred for 18 h at room temperature. Thereaction mixture was diluted with EtOAc (40 mL), then washed with water(2×20 mL). The combined organic layers were dried over anhydrous Na₂SO₄,filtered, and concentrated under vacuum to afford the title compound asa yellow solid (63 mg) which was used without further purification. MS:(ES, m/z): 236 [M+H]⁺.

Step-2:(R)—N-hydroxy-2,4-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed a solution of methyl(R)-2,4-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(134 mg, 0.57 mmol, 1 equiv) in THF/MeOH (4:1, 2 mL). aq. 1N NaOH (1.71mL, 3 equiv) and NH₂OH (50% in water, 1.13 mL, 30 equiv) were added. Theresulting solution was stirred for 15 h at room temperature. The crudeproduct was purified by Prep-HPLC (Column: T3 C18 OBD, 5 μm, 19×150 mm;Mobile Phase A: Water/0.05% TFA; Mobile Phase B: MeCN; Flow rate: 25mL/min; Gradient: 3% B to 30% B in 10 min; Detector: UV 254, 220 nm) toafford the title compound as a TFA salt as an off-white solid (5 mg, 4%yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 7.32-7.17 (m, 2H), 7.06-7.01(s, 1H), 4.56-3.91 (m, 1H), 3.79-3.71 (t, J=17.2 hz, 1H), 3.67-3.51 (t,J=33.2 hz, 1H), 2.89-2.84 (m, 1H), 2.69-2.61 (m, 1H), 2.27-2.25 (d,J=3.6 Hz, 3H), 1.24-1.20 (d, J=8.0 Hz, 3H). MS: (ES, m/z): 237 [M+H]⁺.

Example 17—Preparation of(S)—N-hydroxy-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl (S)-3-bromo-4-(((2-hydroxypropyl)amino)methyl)benzoate

Into a 500-mL round-bottom flask, was placed (2S)-1-aminopropan-2-ol(2.98 g, 39.68 mmol, 1 equiv), MeCN (150 mL) and K₂CO₃ (8.24 g, 59.62mmol, 1.5 equiv). This was followed by the addition of a solution ofmethyl 3-bromo-4-(bromomethyl)benzoate (12.3 g, 39.94 mmol, 1 equiv) inMeCN (20 mL) dropwise with stirring at room temperature over 1 h. Theresulting solution was stirred for 3 h at room temperature. Theresulting mixture was concentrated under vacuum. The residue was dilutedwith EtOAc (300 mL) and washed with water (3×300 mL). The combinedorganic layers were dried and concentrated. The residue was purified bysilica gel chromatography (EtOAc/pet. ether, 1:5) to afford the titlecompound as an off-white solid (5.1 g, 42% yield). MS: (ES, m/z): 302[M+H]⁺.

Step-2: Methyl(S)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 150-mL pressure tank reactor purged and maintained with an inertatmosphere of nitrogen, was placed methyl(S)-3-bromo-4-(((2-hydroxypropyl)amino)methyl)benzoate (5.1 g, 16.88mmol, 1 equiv), isopropanol (120 mL), K₂CO₃ (3.510 g, 25.40 mmol, 1.5equiv) and CuI (966 mg, 5.07 mmol, 0.3 equiv). The resulting solutionwas stirred for 17 h at 110° C. in an oil bath. The resulting mixturewas concentrated under vacuum. The residue was diluted with CH₂Cl₂ (200mL), washed with water (2×200 mL), dried and concentrated. The residuewas purified by silica gel chromatography (EtOAc/pet. ether, 1:2) toafford the title compound as a yellow oil (2.2 g, 59% yield). ¹H-NMR(DMSO, 400 MHz) δ(ppm): 7.57-7.53 (m, 1H), 7.46-7.44 (m, 1H), 7.30-7.27(m, 1H), 3.84-3.76 (m, 5H), 3.09-3.05 (d, J=13.6 Hz, 1H), 2.75-2.66 (s,1H), 1.30-1.29 (d, J=6.4 Hz, 2H). 1.23-1.22 (d, J=6.4 Hz, 3H). MS: (ES,m/z): 222 [M+H]⁺.

Step-3:(S)—N-Hydroxy-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed a solution of methyl(S)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (50mg, 0.23 mmol, 1 equiv) in THF/MeOH (4:1, 1 mL), NH₂OH (50% in water,0.44 mL, 30 equiv) and aq. 1N NaOH (0.45 mL, 2 equiv) were added. Theresulting solution was stirred for 14 h at room temperature. The crudeproduct was purified by Prep-HPLC (Column: Sunfire Prep C18 OBD, 5 μm,19×150 mm; Mobile Phase A: Water/0.05% TFA; Mobile Phase B: MeCN; Flowrate: 25 mL/min; Gradient: 4% B to 18% B in 6 min; Detector: UV 254, 220nm) to afford the title compound as a brown oil (23.5 mg, 31% yield).¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.29 (s, 1H), 9.11 (s, 3H), 7.52-7.44(m, 3H), 4.43-4.39 (d, J=7.2 hz, 1H), 4.32-4.29 (d, J=7.2 hz, 1H),4.19-4.12 (m, 1H), 3.53-3.50 (d, J=6.4 Hz, 1H), 3.29-3.25 (d, J=6.8 Hz,1H), 1.38-1.37 (m, 3H). MS: (ES, m/z): 223 [M+H]⁺.

Example 18—Preparation of(S)—N8-hydroxy-N4-(4-methoxyphenyl)-2-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide

Step-1: Methyl(S)-4-((4-methoxyphenyl)carbamoyl)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 20-mL vial, was placed a solution of methyl(S)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (150mg, 0.68 mmol, 1 equiv) in CH₂Cl₂ (10 mL), 1-isocyanato-4-methoxybenzene(150 mg, 1.01 mmol, 1.2 equiv) and Et₃N (0.18 mg, 3 equiv). Theresulting solution was stirred for 10 h at room temperature. Theresulting mixture was concentrated under vacuum. The residue waspurified by silica gel chromatography (EtOAc/pet. ether, 1:1) to affordthe title compound as a light yellow oil (150 mg, 60% yield). MS: (ES,m/z): 371 [M+H]⁺.

Step-2:(S)—N8-Hydroxy-N4-(4-methoxyphenyl)-2-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide

Into a 10-mL vial, was placed a solution of methyl(S)-4-((4-methoxyphenyl)carbamoyl)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(370 mg, 1 mmol, 1 equiv) in THF/MeOH (4:1, 4 mL). This was followed bythe addition of aq. 1N NaOH (1 mL, 2 equiv). To this was added NH₂OH(50% in water, 1 mL, 30 equiv). The resulting solution was stirred for 3h at room temperature. The crude product was purified by Prep-HPLC(Column: XBridge XP C18 OBD, 5 μm, 19×150 mm; Mobile Phase A:Water/0.05% TFA; Mobile Phase B: MeCN; Flow rate: 0.7 mL/min; Gradient:10% B to 60% B in 7 min; Detector: UV 254 nm) to afford the titlecompound as a light brown solid (106 mg, 73% yield). ¹H-NMR (400 MHz,DMSO-d₆) δ(ppm): 11.14 (br s, 1H), 8.36 (br s, 1H), 7.43-7.38 (m, 2H),7.28-7.24 (m, 2H), 6.81-6.80 (m, 2H), 4.85-4.81 (d, J=15.6 Hz, 1H),4.43-4.39 (d, J=15.6 Hz, 1H), 4.04-4.01 (d, J=12.8 Hz, 1H), 3.76 (s,3H), 3.43-3.37 (m, 2H), 1.32-1.31 (d, J=6.4 Hz, 3H). MS: (ES, m/z): 372[M+H]⁺.

Example 19—Preparation of(S)—N-hydroxy-4-((4-methoxyphenyl)sulfonyl)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-4-((4-methoxyphenyl)sulfonyl)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 50-mL flask, was placed a solution of methyl(S)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (100mg, 0.45 mmol, 1 equiv) in CH₂Cl₂ (20 mL), Et₃N (140 mg, 1.38 mmol, 3equiv) and 4-dimethylaminopyridine (55 mg, 0.45 mmol, 1 equiv), then4-methoxybenzene-1-sulfonyl chloride (140 mg, 0.68 mmol, 1.5 equiv) wasadded at 0° C. The resulting solution was stirred for 4 h at roomtemperature and concentrated under vacuum. The residue was purified bysilica gel chromatography (EtOAc/pet. ether, 1:1) to afford the titlecompound as a yellow solid (80 mg, 45% yield). MS: (ES, m/z): 392[M+H]⁺.

Step-2:(S)—N-Hydroxy-4-((4-methoxyphenyl)sulfonyl)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 10-mL vial, was placed a solution of methyl(S)-4-((4-methoxyphenyl)sulfonyl)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(80 mg, 0.20 mmol, 1 equiv) in THF/MeOH (4:1, 2 mL). This was followedby the addition of aq. 1N NaOH (0.41 mL, 2 equiv) and NH₂OH (50% inwater, 0.41 mL, 30 equiv). The resulting solution was stirred for 2 h atroom temperature. The crude product was purified by Prep-HPLC (Column:XBridge XP C18 OBD, 5 μm, 19×150 mm; Mobile Phase A: Water/0.05% TFA;Mobile Phase B: MeCN; Flow rate: 0.7 mL/min; Gradient: 9% B to 60% B in9 min; Detector: UV 254 nm) to afford the title compound as a pink solid(34 mg, 43% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.17 (br s, 1H),9.01 (br s, 1H), 7.70-7.66 (m, 2H), 7.42-7.39 (m, 1H), 7.33-7.31 (m,1H), 7.24 (s, 1H), 7.06-7.02 (m, 2H), 4.57-4.53 (d, J=16 Hz, 1H),4.25-4.21 (d, J=16 Hz, 1H), 4.04-3.91 (m, 1H), 3.82 (s, 3H), 3.68-3.65(m, 1H), 3.21-3.18 (m, 1H), 1.26-1.25 (m, J=6.4 Hz, 3H). MS: (ES, m/z):393 [M+H]⁺.

Example 20—Preparation of(S)—N-hydroxy-2-methyl-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-2-methyl-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 10-mL vial purged and maintained with Nitrogen, was placed asolution of methyl(S)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (100mg, 0.45 mmol, 1 equiv) in 1,4-dioxane (5 mL), iodobenzene (180 mg, 0.88mmol, 2 equiv), Pd(OAc)₂ (10 mg, 0.04 mmol, 0.1 equiv), Xantphos (50 mg,0.09 mmol, 0.2 equiv) and Cs₂CO₃ (450 mg, 1.38 mmol, 3 equiv). Theresulting solution was stirred for 10 h at 100° C. and then concentratedunder vacuum. The residue was purified by silica gel chromatography(EtOAc/pet. ether, 1:5) to afford the title compound as a light yellowsolid (50 mg, 37% yield). MS: (ES, m/z): 298 [M+H]⁺.

Step-2:(S)—N-Hydroxy-2-methyl-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 10-mL vial, was placed a solution of methyl(S)-2-methyl-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(50 mg, 0.17 mmol, 1 equiv) in THF/MeOH (4:1, 3 mL). This was followedby the addition of aq. 1N NaOH (0.34 mL, 2 equiv) and NH₂OH (50% inwater, 0.34 mL, 30 equiv). The resulting solution was stirred for 3 h atroom temperature. The crude product was purified by Prep-HPLC (Column:XBridge XP C18 OBD, 51 μm, 19×150 mm; Mobile Phase A: Water/0.05% TFA;Mobile Phase B: MeCN; Flow rate: 0.7 mL/min; Gradient: 12% B to 48% B in11 min; Detector: UV 254 nm) to afford the title compound as a brownsolid (12 mg, 25% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 611.09 (brs, 1H), 7.54-7.52 (m, 1H), 7.37-7.35 (m, 1H), 7.34 (s, 1H), 7.29-7.28(m, 2H), 6.95-6.85 (m, 2H), 6.59-6.55 (m, 1H), 4.83-4.79 (d, J=16 Hz,1H), 4.62-4.58 (d, J=16 Hz, 1H), 4.08-4.02 (m, 2H), 3.47-3.41 (m, 1H),1.36-1.24 (m, J=6.4 Hz, 3H). MS: (ES, m/z): 299 [M+H]⁺.

Example 21—Preparation of(S)—N-hydroxy-2,4-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-2,4-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, was placed methyl(S)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (190mg, 0.86 mmol, 1 equiv), formaldehyde (78 mg, 2.60 mmol, 3 equiv),acetic acid (2.5 mL) and NaBH(OAc)₃ (907 mg, 4.30 mmol, 5 equiv). Theresulting solution was stirred for 16 h at room temperature. Thereaction was quenched with water (20 mL). The resulting solution wasextracted with EtOAc (2×20 mL), washed with H₂O (2×15 mL) andconcentrated to afford the title compound as yellow oil (100 mg, 49%yield) which was used without further purification. MS: (ES, m/z): 236[M+H]⁺.

Step-2:(S)—N-hydroxy-2,4-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed methyl(S)-2,4-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(100 mg, 0.43 mmol, 1 equiv), THF/MeOH (4:1, 2.5 mL). To this was addedaq. 1N NaOH (0.85 mL, 0.85 mmol, 2 equiv) and NH₂OH (50% in water, 0.86mL, 12.73 mmol, 30 equiv). The resulting solution was stirred for 3 h atroom temperature. The crude product was purified by Prep-HPLC (Column:XBridge RP C18 OBD, 5 μm, 19×150 mm; Mobile Phase A: Water/0.05% formicacid; Mobile Phase B: MeCN/0.05% TFA; Flow rate: 0.7 mL/min; Gradient:5% B to 40% B in 7 min; Detector: UV 254 nm) to afford the titlecompound as a light brown solid (37 mg, 37% yield). ¹H-NMR (400 MHz,DMSO-d₆) δ(ppm): 11.30 (s, 1H), 10.16 (br s, 1H), 9.19 (s, 1H),7.54-7.52 (m, 1H), 4.46-7.44 (m, 2H), 4.63-4.49 (m, 2H), 3.75-3.48 (m,2H), 3.11-2.70 (m, 3H), 1.37-1.35 (d, J=6.4 Hz, 3H). MS: (ES, m/z): 237[M+H]⁺.

Example 22—Preparation of(S)—N-hydroxy-4-(4-methoxybenzyl)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-4-(4-methoxybenzyl)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, was placed methyl(S)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (100mg, 0.45 mmol, 1 equiv). This was followed by the addition of sodiumhydride (60% in oil, 55 mg, 2.29 mmol, 3 equiv) at 0° C. The mixture wasstirred at room temperature for 1 h and then1-(bromomethyl)-4-methoxybenzene (91 mg, 0.45 mmol, 1 equiv) was added.The mixture was stirred for 19 h at room temperature. The reaction wasthen quenched with water (20 mL). The resulting solution was extractedwith EtOAc (20 mL) and washed with H₂O (2×15 mL). The organic phase wasconcentrated and the residue was purified by silica gel chromatography(EtOAc/pet. ether, 1:3) to afford the title compound as a yellow oil (60mg, 39% yield). MS: (ES, m/z): 342 [M+H]⁺.

Step-2:(S)—N-hydroxy-4-(4-methoxybenzyl)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed methyl(S)-4-(4-methoxybenzyl)-2-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(60 mg, 0.18 mmol, 1 equiv) in THF/MeOH (4:1, 2 mL). To this was addedaq. 1N NaOH (0.35 mL, 0.35 mmol, 2 equiv). To the mixture was addedNH₂OH (50% in water, 0.36 mL, 5.27 mmol, 30 equiv). The resultingsolution was stirred for 3 h at room temperature. The crude product waspurified by Prep-HPLC (Column Sunfire Prep C18 OBD, 5 μm, 19×150 mm;Mobile Phase A: Water/0.05% TFA; Mobile Phase B: MeCN; Flow rate: 0.7mL/min; Gradient: 5% B to 30% B in 6 min; Detector: UV 254 nm) to affordthe title compound as an off-white solid (21 mg, 26% yield). ¹H-NMR (400MHz, DMSO-d₆) δ(ppm): 11.17 (s, 1H), 9.13-9.11 (br s, 1H), 7.57-7.28 (m,5H), 4.67-4.11 (m, 5H), 3.89-3.87 (m, 3H), 3.78-3.56 (m, 2H), 1.34 (s,3H). MS: (ES, m/z): 343 [M+H]⁺.

Example 23—Preparation of(R)—N8-hydroxy-2-isopropyl-N4-(4-methoxyphenyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide

Step-1: Methyl(R)-3-bromo-4-(((2-hydroxy-3-methylbutyl)amino)methyl)benzoate

Into a 500-mL round-bottom flask, was placed(R)-1-amino-3-methylbutan-2-ol (6.41 g, 62.13 mmol, 2 equiv), MeCN (100mL) and K₂CO₃ (6.44 g, 46.60 mmol, 1.5 equiv). This was followed by theaddition of methyl 3-bromo-4-(bromomethyl)benzoate (9.52 g, 30.91 mmol,1 equiv) in several batches. The resulting solution was stirred for 16 hat room temperature. The resulting mixture was concentrated undervacuum. The residue was dissolved in EtOAc (200 mL) and washed with H₂O(2×100 mL). The organic layer was dried over anhydrous Na₂SO₄, filtered,and concentrated. The residue was purified by silica gel chromatography(EtOAc/pet. ether, 3:2) to afford the title compound as a yellow solid(6.48 g, 63% yield). MS: (ES, m/z): 330 [M+H]⁺.

Step-2: Methyl(R)-2-isopropyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 100-mL pressure tank reactor purged and maintained with an inertatmosphere of nitrogen, was placed methyl(R)-3-bromo-4-(((2-hydroxy-3-methylbutyl)amino)methyl)benzoate (4.91 g,14.87 mmol, 1 equiv), isopropanol (50 mL), K₂CO₃ (3.09 g, 22.36 mmol,1.5 equiv) and CuI (1.42 g, 7.46 mmol, 0.5 equiv). The resultingsolution was stirred for 16 h at 110° C. in an oil bath. The resultingmixture was concentrated under vacuum. The residue was dissolved inCH₂Cl₂ (200 mL) and washed with H₂O (3×100 mL). The organic layer wasdried over anhydrous MgSO₄, filtered, and concentrated. The residue waspurified by silica gel chromatography (H₂O/MeCN, 3:1) to afford the TFAsalt of the title compound as a green solid (1.5 g, 40% yield). MS: (ES,m/z): 250 [M+H]⁺.

Step-3: Methyl(R)-2-isopropyl-4-((4-methoxyphenyl)carbamoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, was placed methyl(R)-2-isopropyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(100 mg, 0.40 mmol, 1 equiv), CH₂Cl₂ (1.5 mL) and Et₃N (121 mg, 1.20mmol, 3 equiv). This was followed by the addition of1-isocyanato-4-methoxybenzene (90 mg, 0.60 mmol, 1.5 equiv) at 0° C. Theresulting solution was stirred for 4 h at room temperature, thenconcentrated under vacuum. The residue was purified by silica gelchromatography (EtOAc/pet. ether, 1:2) to afford the title compound as ared oil (110 mg, 69% yield). MS: (ES, m/z): 399 [M+H]⁺.

Step-4:(R)—N8-Hydroxy-2-isopropyl-N4-(4-methoxyphenyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide

Into a 8-mL vial, was placed methyl(R)-2-isopropyl-4-((4-methoxyphenyl)carbamoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(110 mg, 0.28 mmol, 1 equiv) in THF/MeOH (4:1, 1.5 mL). Then NH₂OH (50%in water, 0.56 mL, 8.48 mmol, 30 equiv) and aq. 1N NaOH (0.56 mL, 0.55mmol, 2 equiv) were added at the same time. The resulting solution wasstirred for 16 h at room temperature. The crude product was purified byPrep-HPLC (Column: Sunfire Prep C18 OBD, 5 μm, 19×50 mm; Mobile Phase A:Water/0.05% formic acid; Mobile Phase B: MeCN; Flow rate: 25 mL/min;Gradient: 23% B to 40% B in 7 min; Detector: UV 254, 220 nm) to affordthe title compound as a light pink solid (20.2 mg, 18% yield). ¹H-NMR(400 MHz, DMSO-d₆) δ(ppm): 11.87 (br s, 1H), 8.40 (s, 1H), 7.45-7.41 (m,2H), 7.39-7.33 (m, 1H), 7.28-7.26 (m, 2H), 6.80-6.78 (d, J=9.2 hz, 2H),4.89-4.85 (d, J=16.0 Hz, 1H), 4.46-4.42 (d, J=16.0 Hz, 1H), 4.11-4.08(d, J=13.6 Hz, 1H), 3.68 (s, 3H), 3.59-3.55 (m, 1H), 3.48-3.42 (m, 1H),1.96-1.88 (m, 1H), 1.09-1.06 (m, 6H). MS: (ES, m/z): 400 [M+H]⁺.

Example 24—Preparation of(R)—N8-hydroxy-2-(methoxymethyl)-N4-(4-methoxyphenyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide

Step-1: Methyl(R)-3-bromo-4-(((2-hydroxy-3-methoxypropyl)amino)methyl)benzoate

Into a 500-mL round-bottom flask, was placed a solution of(R)-1-amino-3-methoxypropan-2-ol (5.7 g, 54.22 mmol, 1.1 equiv) in MeCN(150 mL) and K₂CO₃ (10 g, 72.46 mmol, 1.5 equiv). This was followed bythe addition of a solution of methyl 3-bromo-4-(bromomethyl)benzoate(15.2 g, 49.36 mmol, 1 equiv) in MeCN (100 mL) dropwise with stirring atroom temperature. The resulting mixture was stirred for 16 h at roomtemperature. The resulting mixture was concentrated under vacuum. Theresidue was diluted with H₂O (100 mL) and extracted with EtOAc (3×100mL). The organic layer was washed with H₂O (2×100 mL) and concentratedunder vacuum. The residue was purified by silica gel chromatography(EtOAc/pet. ether, 1:4) to afford the title compound as a yellow solid(6.4 g, 39% yield). MS: (ES, m/z): 332 [M+H]⁺.

Step-2: Methyl(R)-2-(methoxymethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 150-mL pressure tank reactor purged and maintained with an inertatmosphere of nitrogen, was placed a solution of methyl(R)-3-bromo-4-(((2-hydroxy-3-methoxypropyl)amino)methyl)benzoate (6.4 g,19.27 mmol, 1 equiv) in isopropanol (130 mL), K₂CO₃ (4.01 g, 29.06 mmol,1.5 equiv) and CuI (1.47 g, 7.74 mmol, 0.4 equiv). The resultingsolution was stirred for 16 h at 110° C. in an oil bath. The resultingmixture was concentrated under vacuum. The residue was diluted with H₂O(100 mL) and extracted with CH₂Cl₂ (3×100 mL). The organic layer waswashed with H₂O (2×100 mL) and concentrated under vacuum. The residuewas purified by C18 chromatography (MeCN/H₂O+0.05% TFA, 88:12) to affordthe TFA salt of the title compound as a yellow solid (3.5 g, 50% yield).MS: (ES, m/z): 252 [M+H]⁺.

Step-3: Methyl(R)-2-(methoxymethyl)-4-((4-methoxyphenyl)carbamoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, was placed a solution of methyl(R)-2-(methoxymethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate.TFA(100 mg, 0.27 mmol, 1 equiv) in CH₂Cl₂ (2 mL), Et₃N (111 mg, 1.10 mmol,4 equiv), a solution of 1-isocyanato-4-methoxybenzene (61 mg, 0.41 mmol,1.5 equiv) in CH₂Cl₂ (0.5 mL). The resulting mixture was stirred for 6 hat room temperature. The resulting solution was diluted with CH₂Cl₂ (10mL) and washed with H₂O (2×15 mL). The combined organic layers weredried over anhydrous MgSO₄, filtered, and concentrated under vacuum. Theresidue was purified by silica gel chromatography (EtOAc/pet. ether,1:2) to afford the title compound as a colorless oil (100 mg, 91%yield). MS: (ES, m/z): 401 [M+H]⁺.

Step-4:(R)—N8-Hydroxy-2-(methoxymethyl)-N4-(4-methoxyphenyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide

Into a 8-mL vial, was placed a solution of methyl(R)-2-(methoxymethyl)-4-((4-methoxyphenyl)carbamoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(100 mg, 0.25 mmol, 1 equiv) in THF/MeOH (4:1, 3 mL). Then aq. 1N NaOH(0.50 mL, 2 equiv) and NH₂OH (50% in H₂O, 0.50 mL, 30 equiv) were addedsimultaneously. The resulting solution was stirred for 2 h at roomtemperature. The crude product was purified by Prep-HPLC (Column:Xbridge Prep C18 OBD, 5 μm, 19×50 mm; Mobile Phase A: Water/0.05% formicacid; Mobile Phase B: MeCN; Flow rate: 23 mL/min; Gradient: 5% B to 39%B in 7 min; Detector: UV 254, 220 nm) to afford the title compound as alight pink solid (62.7 mg, 63% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm):11.15 (br s, 1H), 9.03 (br s, 1H), 8.40 (s, 1H), 7.44-7.7.39 (m, 2H),7.36-7.35 (m, 1H), 7.28-7.24 (m, 2H), 6.81-6.77 (m, 2H), 4.87-4.83 (m,1H), 4.48-4.44 (m, 1H), 4.08-4.03 (m, 2H), 3.68 (s, 3H), 3.61-3.48 (m,3H), 3.35-3.33 (m, 3H). MS: (ES, m/z): 402 [M+H]⁺.

TABLE 6 The following compounds were prepared according to the method ofExample 24, using (S)-1-amino-3-methoxypropan-2-ol. Found Structure M +H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 402 [M + H]⁺ 11.17 (s, 1H), 9.02 (s, 1H), 8.04 (s, 1H),7.45-7.41 (m, 2H), 7.40-7.36 (m, 1H), 7.28-7.24 (m, 2H), 6.81-6.77 (m,2H), 4.87-4.83 (d, J = 15.6 Hz, 1H), 4.48-4.44 (d, J = 15.6 Hz, 1H),4.08-4.03 (m, 2H), 3.68 (s, 3H), 3.61-3.48 (m, 3H), 3.35-3.33 (d, J =9.2 hz, 2H)

Example 25—Preparation of(R)—N8-hydroxy-N4-(4-methoxyphenyl)-2-phenyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide

Step-1: Methyl(R)-3-bromo-4-(((2-hydroxy-2-phenylethyl)amino)methyl)benzoate

Into a 500-mL round-bottom flask, was placed a solution of(R)-2-amino-1-phenylethan-1-ol (10 g, 72.90 mmol, 1.5 equiv) in MeCN(100 mL), then K₂CO₃ (8.7 g, 62.49 mmol, 1.3 equiv) was added. This wasfollowed by the slow addition of a solution of methyl3-bromo-4-(bromomethyl)benzoate (15 g, 48.71 mmol, 1 equiv) in MeCN (120mL). The resulting mixture was stirred overnight at room temperature andthen concentrated under vacuum. The residue was dissolved in EtOAc (350mL) and washed with H₂O (3×100 mL). The organic layer was concentratedunder vacuum and purified by silica gel chromatography (EtOAc/pet.ether, 1:3) to afford the title compound as a yellow solid (9.7 g, 57%yield). MS: (ES, m/z): 364 [M+H]⁺.

Step-2: Methyl(R)-2-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 100-mL sealed tube, was placed a solution of methyl(R)-3-bromo-4-(((2-hydroxy-2-phenylethyl)amino)methyl)benzoate (4.0 g,10.98 mmol, 1 equiv) in isopropanol (80 mL), then K₂CO₃ (3.1 g, 22.43mmol, 2 equiv) was added. This was followed by the addition of CuI (630mg, 3.31 mmol, 0.3 equiv). The resulting mixture was stirred overnightat 110° C. in an oil bath. The solids were filtered out and the filtratewas concentrated under vacuum. The residue was dissolved in EtOAc (300mL) and washed with H₂O (3×150 mL). The organic layer was concentratedunder vacuum. The residue was dissolved in DMF and purified byFlash-Prep-HPLC (Mobile Phase A: Water/0.05% TFA, Mobile Phase B: MeCN;Gradient: 5% B to 20% B in 15 min; Detector: 220, 254 nm) to afford theTFA salt of the title compound as a white solid (1.9 g, 61% yield). MS:(ES, m/z): 284 [M+H]⁺.

Step-3: Methyl(R)-4-((4-methoxyphenyl)carbamoyl)-2-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, was placed a solution of methyl(R)-2-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate*TFA(100 mg, 0.35 mmol, 1 equiv) in CH₂Cl₂ (2.0 mL). This was followed bythe addition of Et₃N (76.13 mg, 0.75 mmol, 3 equiv) at 0° C. To this wasadded 1-isocyanato-4-methoxybenzene (56.2 mg, 0.38 mmol, 1.5 equiv). Theresulting mixture was stirred for 6 h at room temperature and dilutedwith CH₂Cl₂ (20 mL). The resulting mixture was washed with H₂O (3×15 mL)and the combined organic layers were concentrated under vacuum. Theresidue was purified by silica gel chromatography (EtOAc/pet. ether,1:1) to afford the title compound as a yellow oil (105 mg, 69% yield).MS: (ES, m/z): 433 [M+H]⁺.

Step-4:(R)—N8-Hydroxy-N4-(4-methoxyphenyl)-2-phenyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide

Into a 8-mL vial, was placed a solution of methyl(R)-4-((4-methoxyphenyl)carbamoyl)-2-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(105 mg, 0.24 mmol, 1 equiv) in THF/MeOH (4:1, 2.5 mL). Then aq. 1N NaOH(0.48 mL, 2 equiv) and NH₂OH (50% in H₂O, 0.48 mL, 30 equiv) were addedsimultaneously. The resulting solution was stirred for 2 h at roomtemperature. The crude product was purified by Prep-HPLC (Column:Xbridge Prep C18 OBD, 5 μm, 19×50 mm; Mobile Phase A: Water/0.05% formicacid; Mobile Phase B: MeCN; Flow rate: 25 mL/min; Gradient: 30% B to 70%B in 10 min; Detector: UV 254, 220 nm) to afford the title compound as apink solid (48.6 mg, 46% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.13(br s, 1H), 9.02 (s, 1H), 8.51 (s, 1H), 7.55-7.28 (m, 10H), 6.81-6.79(d, 2H), 5.02-4.94 (m, 2H), 4.58-4.54 (d, 1H), 4.26-4.22 (d, 1H),3.71-3.65 (m, 4H). MS: (ES, m/z): 434 [M+H]⁺.

TABLE 7 The following compounds were prepared according to the method ofExample 25, using (S)-2-amino-1-phenylethan-1-ol. Found Structure M + H¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 434 [M + H]⁺ 11.12 (s, 1H), 9.02 (s, 1H), 8.51 (s, 1H),7.57-7.51 (m, 3H), 7.51-7.43 (m, 3H), 7.42-7.33 (m, 2H), 7.32-7.26 (m,2H), 6.81-6.79 (d, J = 8.8 Hz, 2H), 5.02-4.94 (m, 2H), 4.58-4.54 (d, J =15.6 Hz, 1H), 4.23-4.22 (d, J = 14.0 Hz, 1H), 3.71-3.64 (m, 4H)

Example 26—Preparation ofN-hydroxy-4-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1:Methyl-3-bromo-4-[[(1-hydroxy-2-methylpropan-2-yl)amino]methyl]benzoate

Into a 500-mL round-bottom flask, were placed a solution of2-amino-2-methylpropan-1-ol (11.52 g, 129.24 mmol, 2 equiv) in MeCN (150mL), K₂CO₃ (13.40 g, 97.10 mmol, 1.5 equiv). This was followed by theaddition of a solution of methyl 3-bromo-4-(bromomethyl)benzoate (20 g,64.94 mmol, 1 equiv) in MeCN (50 mL) dropwise with stirring at roomtemperature. The resulting solution was stirred for 16 h at roomtemperature, then concentrated under vacuum. The residue was dilutedwith H₂O (200 mL). The resulting solution was extracted with EtOAc(3×200 mL) and the organic layers combined, washed with H₂O (3×200 mL),and concentrated. The residue was purified by silica gel chromatography(EtOAc/pet. ether, 1:4) to afford the title compound as an off-whitesolid (8.7 g, 42% yield). MS: (ES, m/z): 316 [M+H]⁺.

Step 2. Methyl3,3-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 250-mL pressure tank reactor purged and maintained with an inertatmosphere of nitrogen, were placed a solution of methyl3-bromo-4-[[(1-hydroxy-2-methylpropan-2-yl)amino]methyl]benzoate (8.7 g,27.52 mmol, 1 equiv) in isopropanol (150 mL), K₂CO₃ (5.7 g, 41.30 mmol,1.5 equiv) and CuI (1.57 g, 8.26 mmol, 0.3 equiv). The resultingsolution was stirred overnight at 110° C. in an oil bath, thenconcentrated under vacuum. The residue was diluted with H₂O (200 mL).The resulting solution was extracted with EtOAc (3×200 mL) and thecombined organic layers was washed with H₂O (3×200 mL) and concentrated.The residue was purified by silica gel chromatography (EtOAc/pet. ether,1:2) to afford the title compound as a green oil (3.9 g, 60% yield).1H-NMR (400 MHz, DMSO-d6) δ(ppm): 7.63-7.60 (d, J=12.8 Hz, 1H),7.54-7.52 (s, 1H), 7.25-7.23 (d, J=7.6 Hz, 1H), 4.01 (s, 2H), 3.94-3.89(m, 5H), 1.23 (s, 6H). MS: (ES, m/z): 236 [M+H]⁺.

Step-3: Methyl4-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, was placed a solution of methyl3,3-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (100mg, 0.43 mmol, 1 equiv) in THF (2 mL). This was followed by the additionof sodium hydride (60%, 51 mg, 2.12 mmol, 3 equiv). To this was added1-(bromomethyl)-4-methoxybenzene (86 mg, 0.43 mmol, 1 equiv). Theresulting solution was stirred for 22 h at room temperature. Thereaction was then quenched with water (3 mL). The resulting solution wasextracted with EtOAc (3×10 mL), washed with water (3×10 mL) andconcentrated. The residue was purified by silica gel chromatography(EtOAc/pet. ether, 1:4) to afford the title compound as a light yellowoil (100 mg, 66% yield). MS: (ES, m/z): 356 [M+H]⁺.

Step-4:N-Hydroxy-4-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed a solution of methyl4-(4-methoxybenzyl)-3,3-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(100 mg, 0.28 mmol, 1 equiv) in THF/MeOH (4:1, 2.5 mL). This wasfollowed by the addition of NH₂OH (50% in water, 0.56 mL, 30 equiv). Tothis was added aq. 1N NaOH (0.55 mL, 2 equiv). The resulting solutionwas stirred for 2 h at room temperature. The crude product was purifiedby Prep-HPLC (Column: XBridge C18 OBD, 5 μm, 19×150 mm; Mobile Phase A:Water/0.05% TFA; Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient:30% B to 70% B in 10 min; Detector: UV 254, 220 nm) to afford the titlecompound as a TFA salt as a light pink solid (27 mg, 20% yield). ¹H-NMR(400 MHz, DMSO-d₆) δ(ppm): 11.30 (s, 1H), 9.80 (s, 1H), 9.52-8.61 (br,1H), 7.47-7.39 (m, 4H), 7.29-7.03 (m, 3H), 5.02-4.51 (m, 2H), 4.51-4.16(m, 3H) 4.32-4.28 (m, 3H) 3.60-3.45 (m, 1H), 1.75-1.41 (m, 6H). MS: (ES,m/z): 357 [M+H]⁺.

Example 27—Preparation ofN-hydroxy-3,3-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed a solution of methyl3,3-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (100mg, 0.43 mmol, 1 equiv) in THF/MeOH (4:1, 2 mL), followed by theaddition of aq. 1N NaOH (0.85 mL, 2 equiv) and NH₂OH (50% in H₂O, 0.84mL, 30 equiv). The resulting solution was stirred for 3 h at roomtemperature. The crude product was purified by Prep-HPLC (Column:Sunfire Prep C18 OBD, 5 μm, 19×150 mm; Mobile Phase A: Water/0.05% TFA;Mobile Phase B: MeCN; Flow rate: 25 mL/min; Gradient: 2% B to 8% B in 7min; Detector: UV 254, 220 nm) to afford the title compound as the TFAsalt as an off-white solid (57 mg, 39% yield). ¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 11.30 (br, 1H), 9.32 (m, 2H), 9.12 (br, 1H), 7.51 (s, 2H), 7.42(s, 1H), 4.42 (s, 2H), 4.03 (s, 2H), 1.39 (s, 6H) MS: (ES, m/z): 237[M+H]⁺.

Example 28—Preparation ofN-hydroxy-3,3,4-trimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl3,3,4-trimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, was placed a solution of methyl3,3-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (100mg, 0.43 mmol, 1 equiv) in acetic acid (2 mL). This was followed by theaddition of formaldehyde (38 mg, 1.27 mmol, 3 equiv) and NaBH(OAc)₃ (449mg, 2.13 mmol, 5 equiv). The resulting mixture was stirred for 16 h atroom temperature. H₂O (20 mL) was added, then the resulting solution wasextracted with EtOAc (3×30 mL), washed with H₂O (3×20 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under vacuum. The residuewas purified by silica gel chromatography (EtOAc/pet. ether, 1:1) toafford the title compound as a yellow oil (28 mg, 27% yield). MS: (ES,m/z): 250 [M+H]⁺.

Step-2:N-Hydroxy-3,3,4-trimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed a solution of methyl3,3,4-trimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(28.4 mg, 0.11 mmol, 1 equiv) in THF/MeOH (4:1, 1 mL), followed by aq.1N NaOH (0.23 mL, 2 equiv) and NH₂OH (50% in H₂O, 0.23 mL, 30 equiv).The resulting solution was stirred for 3 h at room temperature. Thecrude product was purified by Prep-HPLC (Column: XBridge RP C18 OBD, 5μm, 19×150 mm; Mobile Phase A: Water/0.05% TFA; Mobile Phase B: MeCN;Flow rate: 25 mL/min; Gradient: 5% B to 13% B in 4 min; Detector: UV254, 220 nm) to afford the title compound as the TFA salt as a brown oil(18 mg, 44% yield). ¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 11.30 (br s, 1H),10.17-10.08 (br s, 1H), 9.12 (br, 1H), 7.53-7.41 (m, 3H), 4.74-4.70 (d,J=12.0 Hz, 1H), 4.50-4.28 (m, 2H), 4.07-4.03 (d, J=12.0 Hz, 1H),2.77-2.73 (s, 3H), 1.53 (s, 3H), 1.40 (s, 3H). MS: (ES, m/z): 251[M+H]⁺.

Example 29—Preparation of(S)—N-hydroxy-3-isopropyl-4-(4-methoxybenzyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-3-bromo-4-(((1-hydroxy-3-methylbutan-2-yl)amino)methyl)benzoate

Into a 1-L round-bottom flask, was placed a solution of(S)-2-amino-3-methylbutan-1-ol (23.33 g, 226.15 mmol, 2 equiv) in MeCN(300 mL). This was followed by the addition of a solution of methyl3-bromo-4-(bromomethyl)benzoate (35 g, 113.65 mmol, 1 equiv) in MeCN(200 mL) dropwise with stirring. The resulting solution was stirred for17 h at room temperature, then concentrated under vacuum. The residuewas diluted with H₂O (300 mL), extracted with EtOAc (3×300 mL) and thecombined organic layers were concentrated. The residue was purified bysilica gel chromatography (EtOAc/pet. ether, 1:2) to afford the titlecompound as an off-white solid (20 g, 53% yield). MS: (ES, m/z): 330[M+H]⁺.

Step-2: Methyl(S)-3-isopropyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 500-mL pressure tank reactor purged and maintained with an inertatmosphere of nitrogen, were placed a solution of methyl(S)-3-bromo-4-(((1-hydroxy-3-methylbutan-2-yl)amino)methyl)benzoate (20g, 60.57 mmol, 1 equiv) in isopropanol (350 mL), K₂CO₃ (12.9 g, 93.48,1.5 equiv) and CuI (3.6 g, 18.95 mmol, 0.3 equiv). The resulting mixturewas stirred for 23 h at 110° C. in an oil bath and then concentratedunder vacuum. The residue was diluted with H₂O (300 mL), extracted withCH₂Cl₂ (3×300 mL). The combined organic layers were washed with H₂O(3×300 mL) and concentrated. The residue was purified by silica gelchromatography (EtOAc/pet. ether, 1:1) to afford the title compound as ayellow oil (5.3 g, 35% yield). 1H-NMR (400 MHz, DMSO-d6) δ(ppm):7.66-7.64 (d, J=8.0 Hz, 1H), 7.57 (s, 1H), 7.31-7.29 (d, J=8.0 Hz, 1H),4.43-4.40 (m, 1H), 4.09-3.95 (m, 2H), 3.94-3.81 (s 3H), 3.72-3.69 (m,1H), 2.89-2.86 (m, 1H), 1.88-1.80 (m, 1H), 1.03-0.99 (m, 6H). MS: (ES,m/z): 250 [M+H]⁺.

Step-3: Methyl(S)-3-isopropyl-4-(4-methoxybenzyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, was placed a solution of methyl(S)-3-isopropyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(100 mg, 0.40 mmol, 1 equiv) in THF (2 mL), followed by the addition ofsodium hydride (60% dispersion in oil, 49 mg, 2.04 mmol, 3 equiv) at 0°C. To this was added 1-(bromomethyl)-4-methoxybenzene (81 mg, 0.40 mmol,1 equiv). The resulting solution was stirred for 16 h at roomtemperature, then quenched with water (3 mL). The resulting mixture wasconcentrated under vacuum and diluted with H₂O (10 mL). The resultingsolution was extracted with EtOAc (3×10 mL), washed with H₂O (3×10 mL),and concentrated. The residue was purified by silica gel chromatography(EtOAc/pet. ether, 1:4) to afford the title compound as a yellow oil (70mg, 47% yield). MS: (ES, m/z): 370 [M+H]⁺.

Step-4:(S)—N-hydroxy-3-isopropyl-4-(4-methoxybenzyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed a solution of methyl(S)-3-isopropyl-4-(4-methoxybenzyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(70 mg, 0.19 mmol, 1 equiv) in THF/MeOH (4:1, 2 mL), followed by theaddition of NH₂OH (50% in water, 0.38 mL, 30 equiv) and aq. 1N NaOH(0.38 mL, 2 equiv). The resulting solution was stirred for 2 h at roomtemperature. The crude product was purified by Prep-HPLC (Column:Sunfire Prep C18 OBD, 5 μm, 19×150 mm; Mobile Phase A: Water/0.05% TFA;Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 5% B to 70% B in 7min; Detector: UV 254, 220 nm) to afford the title compound as the TFAsalt as a light brown solid (42 mg, 48% yield). 1H-NMR (400 MHz,DMSO-d6) δ(ppm): 11.40-10.89 (s, 1H), 9.44-8.65 (br, 1H), 7.50-6.68 (m,7H), 4.98-3.89 (m, 7H), 3.75-3.71 (m, 3H), 2.21-1.91 (s, 1H). 1.09-0.89(s, J=6.4 Hz, 6H). MS: (ES, m/z): 371 [M+H]⁺.

TABLE 8 The following compound was prepared according to the method ofExample 29, using (R)-2-amino-3-methylbutan-1-ol. Found Structure M + H¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 371 [M + H]⁺ 11.51-10.85 (br, 1H), 9.71-8.92 (br, 1H),7.51-7.22 (m, 3H), 7.19-6.79 (m, 4H), 4.99-4.09 (m, 5H), 3.86-3.67 (m,3H), 2.27-1.71 (m, 1H), 1.21-0.56 (d, J = 6.0 Hz, 6H)

Example 30—Preparation of(S)—N-hydroxy-3-isopropyl-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-3-isopropyl-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial purged and maintained with an inert atmosphere ofnitrogen, were placed a solution of methyl(S)-3-isopropyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(200 mg, 0.80 mmol, 1 equiv) in toluene (3 mL), iodobenzene (490 mg,2.40 mmol, 3 equiv), Pd(OAc)₂ (40 mg, 0.18 mmol, 0.2 equiv), BINAP (200mg, 0.32 mmol, 0.4 equiv) and Cs₂CO₃ (800 mg, 2.44 mmol, 3 equiv). Theresulting mixture was stirred for 16 h at 110° C. in an oil bath andthen concentrated under vacuum. The residue was diluted with H₂O (10mL). The resulting solution was extracted with EtOAc (3×10 mL), washedwith H₂O (3×10 mL) and then concentrated. The residue was purified bysilica gel chromatography (EtOAc/pet. ether, 1:4) to afford the titlecompound as a brown oil (40 mg, 15% yield). MS: (ES, m/z): 326 [M+H]⁺.

Step-2:(S)—N-Hydroxy-3-isopropyl-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed a solution of methyl(S)-3-isopropyl-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(40 mg, 0.12 mmol, 1 equiv) in THF:MeOH (2 mL, 4:1). This was followedby the addition of NH₂OH (50% in water, 0.25 mL, 30 equiv) and aq. 1NNaOH (0.25 mL, 2 equiv). The resulting solution was stirred for 2 h atroom temperature. The crude product was purified by Prep-HPLC (Column:Sunfire Prep C18 OBD, 5 μm, 19×150 mm; Mobile Phase A: Water/0.05% TFA;Mobile Phase B: MeCN; Flow rate: 25 mL/min; Gradient: 5% B to 78% B in 7min; Detector, UV 254, 220 nm) to afford the title compound as anoff-white solid (7.5 mg, 14% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm):11.08 (s, 1H), 8.97 (s, 1H), 7.49-7.47 (d, J=8.0 Hz, 1H), 7.35-7.33 (d,J=8.0 Hz, 1H), 7.08-7.01 (m, 3H), 6.71-6.69 (d, J=8.0 Hz, 2H), 6.53-6.50(m, 1H), 4.93-4.80 (m, 1H), 4.50-4.23 (m, 3H), 3.98-3.79 (m, 1H),2.11-1.95 (m, 1H), 1.07-0-96 (m, 6H). MS: (ES, m/z): 327 [M+H]⁺.

TABLE 9 The following compound was prepared according to the method ofExample 30, using methyl(R)-3-isopropyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate.Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 327 [M + H]⁺ 11.08-11.05 (s, 1H), 9.03-8.95 (br, 1H),7.49-7.47 (d, J = 8.0 Hz, 1H), 7.35-7.33 (d, J = 8.0 Hz, 1H), 7.11-6.94(m, 3H), 6.79-6.63 (m, 2H), 6.52-6.41 (m, 1H), 4.94- 4.90 (d, J = 17.6Hz, 1H), 4.49-4.32 (m, 3H), 3.94-3.84 (m, 1H), 2.08-1.98 (m, 1H),1.08-0.97 (m, 6H)

Example 31—Preparation of(S)—N8-hydroxy-3-isopropyl-N4-(4-methoxyphenyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide

Step-1: Methyl(S)-3-isopropyl-4-((4-methoxyphenyl)carbamoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, were placed a solution of methyl(S)-3-isopropyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(150 mg, 0.60 mmol, 1 equiv) in CH₂Cl₂ (2.5 mL), Et₃N (183 mg, 1.81mmol, 3 equiv) and 1-isocyanato-4-methoxybenzene (135 mg, 0.91 mmol, 1.5equiv). The resulting mixture was stirred overnight at room temperatureand then concentrated. The residue was purified by silica gelchromatography (EtOAc/pet. ether, 1:2) to afford the title compound as apink solid (250 mg) which was used without further purification. MS:(ES, m/z): 399 [M+H]⁺.

Step-2:(S)—N8-Hydroxy-3-isopropyl-N4-(4-methoxyphenyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide

Into a 8-mL vial, was placed a solution of methyl(S)-3-isopropyl-4-((4-methoxyphenyl)carbamoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(100 mg, 0.25 mmol, 1 equiv) in THF:MeOH (2.0 mL, 4:1), then aq. 1N NaOH(0.75 mL, 2 equiv) and NH₂OH (50% in H₂O, 0.75 mL, 30 equiv) were added.The resulting solution was stirred for 2 h at room temperature. Thecrude product was purified by Prep-HPLC (Column: Sunfire Prep C18 OBD, 5μm, 19×150 mm; Mobile Phase A: Water/0.05% TFA; Mobile Phase B: MeCN;Flow rate: 25 mL/min; Gradient: 4% B to 32% B in 7 min; Detector, UV254, 220 nm) to afford the title compound as a pink solid (75 mg, 75%yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.12 (s, 1H), 9 (s, 1H), 8.14(s, 1H), 7.32-6.76 (m, 7H), 4.91-4.87 (d, 1H), 4.58-4.54 (d, 1H),4.35-4.26 (m, 3H), 3.69-3.67 (s, 3H), 2-1.97 (s, 1H), 0.99-0.97 (d, 3H,J=8.0 Hz), 0.95-0.93 (d, 3H, J=8.0 Hz). MS: (ES, m/z): 400 [M+H]⁺.

TABLE 10 The following compound was prepared according to the method ofExample 31, using methyl(R)-3-isopropyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate.Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 400 [M + H]⁺ 11.12 (br s, 1H), 8.14 (s, 1H), 7.39-7.30 (s,2H), 7.29-7.12 (m, 3H), 6.83-6.71 (m, 2H), 4.96-4.82 (d, J = 23.2 Hz,1H), 4.62-4.48 (d, J = 23.2 Hz, 1H), 4.41-4.21 (m, 3H), 3.67 (s, 3H),2.09-1.84 (m, 1H), 1.04-0.87 (m, 6H)

Example 32—Preparation of(S)—N-hydroxy-3-isopropyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed a solution of methyl(S)-3-isopropyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(100 mg, 0.40 mmol, 1 equiv) in THF:MeOH (2 mL, 4:1). This was followedby the addition of NH₂OH (50% in H₂O, 398 mg, 12.05 mmol, 30 equiv) andaq. 1N NaOH (32 mg, 0.80 mmol, 2 equiv). The resulting solution wasstirred for 2 h at room temperature. The crude product was purified byPrep-HPLC (Column: XBridge RP C18 OBD, 5 μm, 19×50 mm; Mobile Phase A:Water/0.05% formic acid; Mobile Phase B: MeCN/0.05% formic acid; Flowrate: 23 mL/min; Gradient: 2% B to 10% B in 7 min; Detector, UV 254, 220nm) to afford the title compound as a pink solid (99 mg, 68% yield).¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.30 (s, 1H), 9.31 (s, 1H), 7.53-7.40(m, 3H), 4.55-4.34 (m, 3H), 4-3.95 (m, 1H), 3.51 (s, 1H), 2.10-2.06 (m,1H), 1.03-1.02 (d, J=4.0 Hz, 3H), 0.98-0.96 (d, J=8.0 Hz, 3H). MS: (ES,m/z): 250 [M+H]⁺.

TABLE 11 The following compound was prepared according to the method ofExample 32, using methyl(R)-3-isopropyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate.Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 250 [M + H]⁺ 11.31 (br s, 1H), 9.42-9.31 (br s, 1H),9.11-9.04 (m, 2H), 7.54-7.49 (m, 2H), 7.41 (s, 1H), 4.56-4.35 (m, 3H),4.01- 3.96 (m, 1H), 3.52 (s, 1H), 2.13-2.05 (m, 1H), 1.04-0.97 (m, 6H)

Example 33—Preparation of(S)—N-hydroxy-3-isopropyl-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-3-isopropyl-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, were placed a solution of methyl(S)-3-isopropyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(150 mg, 0.60 mmol, 1 equiv) in acetic acid (3.0 mL) andparaformaldehyde (180 mg, 5.62 mmol, 10 equiv). The resulting solutionwas stirred for 2 h at room temperature. Then NaBH(OAc)₃ (2.54 g, 20equiv) was added at 0° C. The reaction was stirred for an additional 1day at room temperature and then concentrated under vacuum to afford thetitle compound as light yellow oil (190 mg) which was used withoutpurification. MS: (ES, m/z): 264 [M+H]⁺.

Step-2:(S)—N-Hydroxy-3-isopropyl-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed a solution of methyl(S)-3-isopropyl-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(90 mg, 0.34 mmol, 1 equiv) in THF:MeOH (2 mL, 4:1), followed by theaddition of NH₂OH (50% in water, 0.67 mL, 10.27 mmol, 30 equiv) and aq.1N NaOH (0.68 mL, 2 equiv). The resulting solution was stirred for 2 hat room temperature. The crude product was purified by Prep-HPLC(Column: Sunfire Prep C18 OBD, 5 μm, 19×150 mm; Mobile Phase A:Water/0.05% TFA; Mobile Phase B: MeCN; Flow rate: 25 mL/min; Gradient:3% B to 10% B in 7 min; Detector, UV 254, 220 nm) to afford the titlecompound as an orange semi-solid (35 mg, 27% yield). ¹H-NMR (400 MHz,DMSO-d₆) δ(ppm): 11.31 (s, 1H), 10.25-9.78 (s, 1H), 9.14-9.05 (s, 1H),7.56-7.33 (m, 3H), 4.91-4.73 (s, 0.5H), 4.68-4.60 (d, 2.5H), 4.60-4.33(m, 0.4H), 4.30-4.16 (m, 0.6H), 3.99-3.22 (m, 2H), 3.67-2.64 (s, 2H),2.51-2.33 (m, 0.7H), 2.11-1.88 (m, 0.3H), 1.10-0.89 (m, 6H). MS: (ES,m/z): 265 [M+H]⁺.

TABLE 12 The following compound was prepared according to the method ofExample 33, using methyl(R)-3-isopropyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate.Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 265 [M + H]⁺ 11.30 (br s, 1H), 9.13 (br s, 1H), 7.58-7.27 (m,3H), 4.84- 4.80 (d, J = 12.0 Hz, 1H), 4.49-4.32 (m, 3H), 4.13-3.81 (m,1H), 2.99-2.88 (s, 2H), 2.61-2.54 (s, 1H), 2.36 (s, 1H), 1.10- 1.09 (d,J = 3.0 Hz, 6H)

Example 34—Preparation of(S)—N-hydroxy-3-isopropyl-4-(pyridin-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-3-isopropyl-4-(pyridin-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 40-mL sealed tube purged and maintained with an inert atmosphereof nitrogen, was placed a solution of methyl(S)-3-isopropyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(250 mg, 1.00 mmol, 1 equiv) in toluene (15 mL), 4-bromopyridine (1.56g, 8.00 mmol, 8 equiv), RuPhos (187 mg, 0.40 mmol, 0.4 equiv), Pd₂(dba)₃(189 mg, 0.18 mmol, 0.2 equiv) and sodium tert-butoxide (480 mg, 5.00mmol, 5 equiv). The resulting solution was stirred for 20 h at 110° C.in an oil bath. The resulting solution was diluted with H₂O (10 mL) andextracted with EtOAc (3×10 mL). The combined organic layers were washedwith H₂O (3×10 mL) and concentrated under vacuum. The residue waspurified by silica gel chromatography (EtOAc/pet. ether, 1:1) to affordthe title compound as a brown oil (15 mg, 5% yield). MS: (ES, m/z):327[M+H]⁺.

Step-2:(S)—N-Hydroxy-3-isopropyl-4-(pyridin-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed a solution of methyl(S)-3-isopropyl-4-(pyridin-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(15 mg, 0.05 mmol, 1 equiv) in THF/MeOH (4:1, 1.5 mL). This was followedby the addition of NH₂OH (50% in water, 0.1 mL, 30 equiv). To this wasadded aq. 1N NaOH (0.1 mL, 2 equiv). The resulting solution was stirredfor 3 h at room temperature. The crude product was purified by Prep-HPLC(Column: Sunfire Prep C18 OBD, 5 μm, 19×150 mm; Mobile Phase A:Water/0.05% TFA; Mobile Phase B: MeCN; Flow rate: 25 mL/min; Gradient:5% B to 45% B in 8 min; Detector: UV 254, 220 nm) to afford the titlecompound as a brown oil (2 mg, 12% yield). ¹H-NMR (400 MHz, DMSO-d₆)δ(ppm): 11.18 (br s, 1H), 9.05 (br s, 1H), 8.25-8.16 (m, 2H), 7.65-7.63(m, 1H), 7.51-7.40 (m, 2H), 7.32 (s, 1H), 7.29-7.17 (m, 2H), 7.07-7.04(m, 1H), 6.93-6.91 (m, 1H), 5.23-5.18 (m, 1H), 4.92-4.79 (m, 1H),4.58-4.44 (m, 3H), 2.15-2.12 (m, 1H), 1.06-1.04 (d, J=3.2 Hz, 3H),0.94-0.92 (d, J=3.2 Hz, 3H). MS: (ES, m/z): 328[M+H]⁺.

TABLE 13 The following compounds were prepared according to the methodof Example 34. Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 328 [M + H]⁺ 11.28 (br s, 1H), 8.29 (s, 1H), 8.04-8.02 (d, J= 2.6 Hz, 1H), 7.96-7.94 (d, J = 3.6 Hz, 1H), 7.74-7.71 (m, 1H),7.62-7.56 (m, 1H), 7.42-7.40 (m, 1H), 7.18- 7.14 (m, 1H), 5.13-5.08 (m,1H), 4.72-4.68 (m, 1H), 4.51-41 (m, 2H), 4.32-4.19 (m, 1H), 2.12-2.07(m, 1H), 0.98-0.96 (d, J = 3.2 hz, 3H), 0.89-0.87 (d, J = 3.6 Hz, 3H)

(ES, m/z): 328 [M + H]⁺ 11.17 (br s. 1H), 8.02-8.01 (br s, 1H),7.96-7.84 (m, 1H), 7.71-7.68 (m, 1H), 7.60-7.58 (d, J = 3.6 Hz, 1H),7.16 (s, 2H), 6.96-6.85 (m, 1H), 5.21-4.97 (m, 2H), 4.84-4.72 (m, 1H),4.63-4.48 (m, 2H), 2.15- 2.13 (m, 1H), 1.07-1.05 (d, J = 3.2 hz, 3H),0.97- 0.96 (d, J = 3.2 hz, 3H)

Example 35—Preparation of(S)—N8-hydroxy-N4-(4-methoxyphenyl)-3-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide

Step-1: Methyl(S)-3-bromo-4-(((1-hydroxypropan-2-yl)amino)methyl)benzoate

Into a 500-mL round-bottom flask, was placed a solution of methyl3-bromo-4-(bromomethyl)benzoate (10 g, 32.47 mmol, 1 equiv) in THF (150mL), (S)-2-aminopropan-1-ol (2.4 g, 31.95 mmol, 1 equiv) and K₂CO₃ (6.7g, 1.5 equiv). The resulting solution was stirred for 3 h at roomtemperature, then concentrated under vacuum. The residue was washed withEtOAc/pet. ether (1:10, 20 mL) to afford the title compound as anoff-white solid (5 g, 51% yield). MS: (ES, m/z): 302 [M+H]⁺.

Step-2: Methyl(S)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of methyl(S)-3-bromo-4-(((1-hydroxypropan-2-yl)amino)methyl)benzoate (3.2 g,10.59 mmol, 1 equiv) in isopropanol (35 mL), K₂CO₃ (2.20 g, 15.92 mmol,1.5 equiv) and CuI (610 mg, 3.20 mmol, 0.3 equiv). The resultingsolution was stirred for 19 h at 110° C. in an oil bath. The resultingmixture was concentrated under vacuum, diluted with EtOAc (300 mL), andwashed with H₂O (3×100 mL). The organic phase was concentrated and theresidue was purified by silica gel chromatography (EtOAc/pet. ether,1:4) to afford the title compound as a light yellow oil (1 g, 43%yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 7.57-7.50 (m, 1H), 7.45 (s,1H), 7.35-7.29 (m, 1H), 4.27-4.19 (m, 1H), 3.99-3.81 (m, 5H), 3.37-3.21(m, 2H), 3.17-3.10 (s, 1H), 1.05-0.94 (d, J=6.4 Hz, 3H). MS: (ES, m/z):222 [M+H]⁺.

Step-3: Methyl(S)-4-((4-methoxyphenyl)carbamoyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 25-mL flask, was placed a solution of methyl(S)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (100mg, 0.45 mmol, 1 equiv) in CH₂Cl₂ (10 mL), 1-isocyanato-4-methoxybenzene(100 mg, 0.67 mmol, 1.5 equiv), Et₃N (150 mg, 1.48 mmol, 3 equiv) and4-dimethylaminopyridine (50 mg, 0.41 mmol, 1 equiv). The resultingsolution was stirred for 10 h at room temperature. The resulting mixturewas concentrated under vacuum. The residue was purified by silica gelchromatography (EtOAc/pet. ether, 1:1) to afford the title compound as alight yellow oil (30 mg, 18% yield). MS: (ES, m/z): 371 [M+H]⁺.

Step-4:(S)—N8-hydroxy-N4-(4-methoxyphenyl)-3-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide

Into a 10-mL vial, was placed a solution of methyl(S)-4-((4-methoxyphenyl)carbamoyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(100 mg, 0.27 mmol, 1 equiv) in THF/MeOH (3 mL, 4:1), followed by theaddition of aq. 1N NaOH (0.54 mL, 2 equiv.) and NH₂OH (50% in water,0.54 mL, 30 equiv.). The resulting solution was stirred for 2 h at roomtemperature. The crude product was purified by Prep-HPLC (Column:XBridge XP C18 OBD, 5 μm, 19×150 mm; Mobile Phase A: Water/0.05% TFA;Mobile Phase B: MeCN; Flow rate: 0.7 mL/min; Gradient: 13% B to 46% B in9 min; Detector, UV 254, 220 nm) to afford the title compound as a pinksolid (81 mg, 81% yield). ¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 11.12 (br s,1H), 8.19 (br s, 1H), 7.31-7.25 (m, 4H), 7.19 (s, 1H), 6.80-6.77 (m,2H), 4.86-4.80 (m, 1H), 4.67-4.61 (m, 2H), 4.29-4.13 (m, 2H), 3.68 (s,3H), 1.23-1.15 (m, 3H). MS: (ES, m/z): 372 [M+H]⁺.

TABLE 14 The following compound was prepared according to the method ofExample 35, using (R)-2-aminopropan-1-ol. Found Structure M + H ¹H-NMR(400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 372 [M + H]⁺ 11.11 (br s, 1H), 8.18 (s, 1H), 7.33-7.24 (m,4H), 7.18 (s, 1H), 6.80-6.76 (m, 2H), 4.85-4.80 (m, 1H), 4.69- 4.61 (m,2H), 4.27-4.15 (m, 2H), 3.68 (s, 3H), 1.16- 1.15 (m, 3 H)

Example 36—Preparation of(S)—N-hydroxy-4-((4-methoxyphenyl)sulfonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-4-((4-methoxyphenyl)sulfonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, was placed a solution of methyl(S)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (100mg, 0.45 mmol, 1 equiv) in CH₂Cl₂ (3 mL), Et₃N (137 mg, 1.35 mmol, 3equiv), 4-dimethylaminopyridine (110 mg, 0.90 mmol, 2 equiv) and4-methoxybenzene-1-sulfonyl chloride (234 mg, 1.13 mmol, 2.50 equiv).The resulting solution was stirred for 17 h at room temperature and thenconcentrated under vacuum. The residue was diluted with H₂O (10 mL),extracted with EtOAc (20 mL) and the organic layer concentrated undervacuum. The residue was purified by silica gel chromatography(EtOAc/pet. ether, 1:2) to afford the title compound as a light yellowoil (90 mg, 51% yield). MS: (ES, m/z): 392 [M+H]⁺.

Step-2:(S)—N-Hydroxy-4-((4-methoxyphenyl)sulfonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed methyl(S)-4-((4-methoxyphenyl)sulfonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(90 mg, 0.23 mmol, 1 equiv) in THF/MeOH (4:1, 2 mL). To this was addedaq. 1N NaOH (0.46 mL, 2 equiv) and NH₂OH (50% in water, 0.46 mL, 30equiv). The resulting solution was stirred for 3 h at room temperature.The crude product was purified by Prep-HPLC (Column: XBridge XP C18 OBD,5 μm, 19×150 mm; Mobile Phase A: Water/0.05% TFA; Mobile Phase B: MeCN;Flow rate: 0.7 mL/min; Gradient: 5% B to 55% B in 7 min; Detector, UV254, 220 nm) to afford the title compound as an off-white solid (64 mg,71% yield). ¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 11.07 (br s, 1H),7.36-7.33 (m, 2H), 7.28-7.25 (m, 1H), 7.21-7.18 (m, 1H), 6.80 (s, 1H),6.75-6.72 (m, 2H), 4.90-4.84 (d, J=17.4 Hz, 1H), 4.60-4.54 (d, J=17.4Hz, 1H), 4.32-4.29 (m, 1H), 4.17-4.13 (m, 1H), 4.09-3.99 (m, 1H), 3.71(m, 4H), 1.13-1.11 (m, J=6.6 Hz, 3H). MS: (ES, m/z): 393 [M+H]⁺.

TABLE 15 The following compound was prepared according to the method ofExample 36, using methyl(R)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate.Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 393 [M + H]⁺ 11.07 (br s, 1H), 8.98 (s, 1H), 7.36-7.33 (m,2H), 7.28-7.25 (m, 1H), 7.20-7.18 (m, 1H), 6.80 (s, 1H), 6.79-6.72 (m,2H), 4.89-4.85 (m, 1H), 4.59-4.55 (m, 1H), 4.31-4.26 (1, 2H), 4.16-4.10(m, 1H), 4.02-3.98 (m, 1H), 3.71 (s, 3H), 1.13-1.06 (m, 3 H)

Example 37—Preparation of(S)—N-hydroxy-4-(4-methoxybenzyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-4-(4-methoxybenzyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, was placed a solution of methyl(S)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (100mg, 0.45 mmol, 1 equiv) in THF (3 mL). This was followed by the additionof sodium hydride (90 mg, 3.75 mmol, 5 equiv, 60% dispersion in oil) and1-(bromomethyl)-4-methoxybenzene (91 mg, 0.45 mmol, 1 equiv). Theresulting solution was stirred for 17 h at room temperature. Thereaction was then quenched by the addition of H₂O (2 mL). The resultingmixture was concentrated under vacuum. The residue was purified bysilica gel chromatography (EtOAc/pet. ether, 1:3) to afford the titlecompound as a light yellow oil (68 mg, 44% yield). MS: (ES, m/z): 342[M+H]⁺.

Step-2:(S)—N-Hydroxy-4-(4-methoxybenzyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed methyl(S)-4-(4-methoxybenzyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(67.6 mg, 0.20 mmol, 1 equiv) in THF/MeOH (4:1, 2 mL). To this was addedaq. 1N NaOH (0.40 ml, 2 equiv) and NH₂OH (50% in water, 0.40 mL, 30equiv). The resulting solution was stirred for 3 h at room temperature.The crude product was purified by Prep-HPLC (Column: XBridge XP C18 OBD,5 μm, 19×150 mm; Mobile Phase A: Water/0.05% TFA; Mobile Phase B: MeCN;Flow rate: 0.7 mL/min; Gradient: 5% B to 25% B in 7 min; Detector, UV254, 220 nm) to afford the title compound as a brown solid (58 mg, 85%yield). ¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 11.35 (br, 1H), 10.65 (br,1H), 7.52-7.25 (m, 5H), 7.02-6.99 (m, 2H), 4.89-4.28 (m, 6H), 3.86-3.67(m, 4H), 1.48-1.46 (d, J=6 Hz, 3H). MS: (ES, m/z): 343 [M+H]⁺.

TABLE 16 The following compound was prepared according to the method ofExample 37, using methyl(R)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate.Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 343 [M + H]⁺ 11.31 (s, 1H), 10.83-10.06 (br, 1H), 9.73-8.57(br, 1H), 7.51-7.33 (m, 5H), 7.13-6.92 (m, 2H), 5.13-3.96 (m, 7H), 3.78(s, 3H), 1.47 (s, 3H)

Example 38—Preparation of(S)—N-hydroxy-3-methyl-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-3-methyl-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 25-mL vial purged and maintained with an inert atmosphere ofnitrogen, were placed a solution of methyl(S)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (300mg, 1.36 mmol, 1 equiv) in 1,4-dioxane (8 mL), iodobenzene (827 mg, 4.05mmol, 3 equiv), Xantphos (312 mg, 0.54 mmol, 0.4 equiv), Cs₂CO₃ (1.33 g,4.05 mmol, 3 equiv) and Pd(OAc)₂ (61 mg, 0.27 mmol, 0.2 equiv). Theresulting solution was stirred for 21 h at 110° C. in an oil bath. Theresulting mixture was concentrated under vacuum and the residue waspurified by silica gel chromatography (EtOAc/pet. ether, 1:3) to affordthe title compound as a light yellow oil (41 mg, 10% yield). MS: (ES,m/z): 298 [M+H]⁺.

Step-2:(S)—N-hydroxy-3-methyl-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed methyl(S)-3-methyl-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(41 mg, 0.14 mmol, 1 equiv) in THF/MeOH (4:1, 2 mL). To this was addedaq. 1N NaOH (0.28 mL, 2 equiv) and NH₂OH (50% in water, 0.28 mL, 30equiv). The resulting solution was stirred for 3 h at room temperature.The crude product was purified by Prep-HPLC (Column: XBridge XP C18 OBD,5 μm, 19×150 mm; Mobile Phase A: Water/0.05% TFA; Mobile Phase B: MeCN;Flow rate: 0.7 mL/min; Gradient: 5% B to 80% B in 7 min; Detector, UV254, 220 nm) to afford the title compound as a light brown solid (13 mg,33% yield). ¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 11.10-11 (br s, 1H),7.49-7.46 (m, 1H), 7.34-7.32 (m, 1H), 7.10-7.04 (m, 3H), 6.66-6.64 (m,2H), 6.56-6.51 (m, 1H), 5.03-4.97 (d, J=17.4 Hz, 1H), 4.41-4.20 (m, 4H),1.20-1.18 (d, J=5.7 Hz, 3H). MS: (ES, m/z): 299 [M+H]⁺.

TABLE 17 The following compound was prepared according to the method ofExample 38, using methyl(R)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate.Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 299 [M + H]⁺ 11.09 (br s, 1H), 7.49-7.47 (m, 1H), 7.34-7.32(m, 1H), 7.10-7.05 (m, 3H), 6.66-6.64 (m, 2H), 6.56-6.52 (m, 1H),5.03-4.95 (d, J = 17.4 Hz, 1H), 4.49-4.20 (m, 4H), 1.23- 1.18 (d, J =5.7 Hz, 3H)

Example 39—Preparation of(S)—N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed a solution of methyl(S)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (50mg, 0.23 mmol, 1 equiv) in THF/MeOH (4:1, 1 mL), NH₂OH (50% in water,0.44 mL, 30 equiv) and aq. 1N NaOH (0.45 mL, 2 equiv). The resultingsolution was stirred for 14 h at room temperature. The crude product waspurified by Prep-HPLC (Column: Sunfire Prep C18 OBD, 5 μm, 19×150 mm;Mobile Phase A: Water/0.05% TFA; Mobile Phase B: MeCN; Flow rate: 25mL/min; Gradient: 4% B to 20% B in 7 min; Detector, UV 254, 220 nm) toafford the title compound as the TFA salt as a pink solid (9 mg, 11%yield). ¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 11.31 (s, 1H), 9.12 (s, 3H),7.53 (s, 2H), 7.44 (s, 1H), 4.42-4.33 (m, 3H), 3.79-3.74 (t, J=9.8 Hz,2H), 1.24-1.23 (d, J=3.0 Hz, 3H). MS: (ES, m/z): 223 [M+H]⁺.

TABLE 18 The following compound was prepared according to the method ofExample 39, using methyl(R)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate.Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 223 [M + H]⁺ 11.30 (s, 1H), 9.50-9.44 (s, 1H), 9.12-8.99 (s,2H), 7.53- 7.44 (d, J = 17.8 Hz, 3H), 4.42-4.33 (m, 3H), 3.79-3.75 (d, J= 20.4 Hz, 2H), 1.29-1.22 (s, 3H)

Example 40—Preparation of(S)—N-hydroxy-3,4-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-3,4-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, was placed a solution of methyl(S)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (100mg, 0.45 mmol, 1 equiv) in acetic acid (1.5 mL). This was followed bythe addition of formaldehyde (41 mg, 1.37 mmol, 3 equiv). The mixturewas stirred for 2 h at room temperature and NaBH(OAc)₃ (477 mg, 2.26mmol, 5 equiv) was added in portions at 0° C. The resulting solution wasstirred for 18 h at room temperature. EtOAc was added and the resultingmixture was washed with H₂O (2×20 mL). The organic layer was dried overanhydrous Na₂SO₄, filtered, and concentrated under vacuum to afford thetitle compound as a brown oil (70 mg, 66% yield). MS: (ES, m/z): 236[M+H]⁺.

Step-2:(S)—N-Hydroxy-3,4-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed a solution of methyl(S)-3,4-dimethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(85 mg, 0.36 mmol, 1 equiv) in THF/MeOH (4:1, 1.5 mL), then aq. 1N NaOH(1.1 mL, 3 equiv) and NH₂OH (50% in water, 0.72 mL, 30 equiv) were addedsimultaneously. The resulting solution was stirred for 15 h at roomtemperature. The crude product was purified by Prep-HPLC (Column:Atlantis T3 C18, 5 μm, 19×150 mm; Mobile Phase A: Water/0.05% TFA;Mobile Phase B: MeCN; Flow rate: 25 mL/min; Gradient: 2% B to 2% B in 13min; Detector, UV 254, 220 nm) to afford the title compound as a TFAsalt as an orange oil (9 mg, 7% yield). ¹H-NMR (300 MHz, DMSO-d₆)δ(ppm): 11.31 (s, 1H), 10.08-10.06 (s, 1H), 9.14 (s, 1H), 7.55-7.43 (m,3H), 4.63-4.41 (m, 2H), 4.16-4.10 (m, 2H), 3.84-3.61 (s, 1H), 2.85 (s,1H), 2.67-2.64 (s, 2H), 1.54-1.29 (m, 3H). MS: (ES, m/z): 237 [M+H]⁺.

TABLE 19 The following compound was prepared according to the method ofExample 40, using methyl(R)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate.Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 237 [M + H]⁺ 11.31 (s, 1H), 10.67-10.23 (br, 1H), 9.14 (br,1H), 7.54-7.43 (m, 3H), 4.70-4.51 (m, 2H), 4.37-3.70 (m, 3H), 2.94-2.59(m, 3H), 1.40-1.27 (d, J = 52.7, 3H)

Example 41—Preparation of(S)—N-hydroxy-3-methyl-4-(o-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-3-methyl-4-(o-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL sealed tube purged and maintained with an inert atmosphereof nitrogen, was placed a solution of methyl(S)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (200mg, 0.90 mmol, 1 equiv) in toluene (3 mL), 1-bromo-2-methylbenzene (462mg, 2.70 mmol, 3 equiv), Cs₂CO₃ (887 mg, 2.70 mmol, 3 equiv), BINAP (225mg, 0.36 mmol, 0.4 equiv) and Pd(OAc)₂ (41 mg, 0.18 mmol, 0.2 equiv).The resulting solution was stirred for 20 h at 110° C. in an oil bath.The resulting mixture was concentrated under vacuum. The resultingsolution was diluted with H₂O (10 mL) and extracted with EtOAc (3×10mL). The combined organic layers were washed with H₂O (2×10 mL) andconcentrated under vacuum. The residue was purified by silica gelchromatography (EtOAc/pet. ether, 1:5) to afford the title compound as ayellow oil (30 mg, 11% yield). MS: (ES, m/z): 312[M+H]⁺.

Step-2:(S)—N-hydroxy-3-methyl-4-(o-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed a solution of methyl(S)-3-methyl-4-(o-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(30 mg, 0.10 mmol, 1 equiv) in THF/MeOH (4:1, 3 mL). This was followedby the addition of NH₂OH (50% in water, 0.19 mL, 30 equiv) and aq. 1NNaOH (0.19 mL, 2 equiv). The resulting solution was stirred for 2 h atroom temperature. The crude product was purified by Prep-HPLC (Column:Xbridge Prep C18 OBD, m, 19×150 mm; Mobile Phase A: Water/0.05% formicacid; Mobile Phase B: MeCN; Flow rate: 0.7 mL/min; Gradient: 15% B to60% B in 7 min; Detector: UV 254, 220 nm) to afford the title compoundas a white solid (8.2 mg, 24% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm):7.44-7.33 (m, 2H), 7.30 (m, 1H), 7.29-7.12 (m, 3H), 6.98-6.96 (m, 1H),4.46-4.39 (m, 2H), 4.31-4.16 (m, 1H), 4.08-4.04 (m, 1H), 3.70 (s, 1H),2.18 (s, 3H), 1.04-1.02 (d, J=8.0 Hz, 3H). MS: (ES, m/z): 313 [M+H]⁺.

Example 42—Preparation of(S)—N-hydroxy-4-(2-methoxyphenyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-4-(2-methoxyphenyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 100-mL round-bottom flask, was placed a solution of methyl(S)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (220mg, 0.99 mmol, 1 equiv) in CH₂Cl₂ (30 mL), (2-methoxyphenyl)boronic acid(452 mg, 2.97 mmol, 3 equiv), Et₃N (300 mg, 2.97 mmol, 3 equiv) andCu(OAc)₂ (182 mg, 1.00 mmol, 1 equiv). To the above oxygen gas wasintroduced in. The resulting solution was stirred for 27 h at roomtemperature and then washed with H₂O (3×10 mL). The organic layers wasconcentrated under vacuum. The residue was purified by silica gelchromatography (EtOAc/pet. ether, 1:3) to afford the title compound as asolid (50 mg, 15% yield MS: (ES, m/z): 328 [M+H]⁺.

Step-2:(S)—N-Hydroxy-4-(2-methoxyphenyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed a solution of methyl(S)-4-(2-methoxyphenyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(50 mg, 0.15 mmol, 1 equiv) in THF/MeOH (4:1, 1.5 mL). This was followedby the addition of NH₂OH (50% in water, 0.30 mL, 30 equiv). To this wasadded aq. 1N NaOH (0.30 mL, 2 equiv). The resulting solution was stirredfor 2 h at room temperature. The crude product was purified by Prep-HPLC(Column: Xbridge Prep C18 OBD, 5 μm, 119×150 mm; Mobile Phase A:Water/0.05% formic acid; Mobile Phase B: MeCN; Flow rate: 0.7 mL/min;Gradient: 5% B to 60% B in 8 min; Detector: UV 254, 220 nm) to affordthe title compound as a yellow solid (3.9 mg, 7% yield). ¹H-NMR (400MHz, DMSO-d₆) δ(ppm): 11.24 (br s, 1H), 7.40-7.38 (m, 1H), 7.33-7.31 (m,1H), 7.26-7.20 (m, 1H), 7.15-6.78 (m, 4H), 4.74-4.70 (d, J=16.0 Hz, 1H),4.35-4.31 (m, 2H), 4.16-4.13 (m, 2H), 3.87 (s, 3H), 1.14-1.13 (d, J=4.0Hz, 3H). MS: (ES, m/z): 329 [M+H]⁺.

TABLE 20 The following compounds were prepared according to the methodof Example 42. Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 317 [M + H]⁺ 11.09 (s, 1H), 8.98 (s, 1H), 7.46-7.44 (m, 1H),7.33- 7.31 (m, 1H), 7.09 (s, 1H), 6.92-6.87 (m, 2H), 6.63- 6.60 (m, 2H),5.00-4.96 (m, 1H), 4.36-4.26 (m, 2H), 4.21-4.15 (m, 2H), 1.22-1.17 (m,3H)

(ES, m/z): 317 [M + H]⁺ 11.08 (s, 1H), 8.98 (s, 1H), 7.50-7.48 (d, J = 8Hz, 1H), 7.33-7.30 (m, 1H), 7.09-7.03 (m, 2H), 6.49-6.46 (m, 1H),6.43-6.38 (d, J = 8 Hz, 1H), 6.33-6.28 (m, 1H), 5.03-4.99 (d, J = 8 Hz,1H), 4.40-4.27 (m, 2H), 4.26-4.18 (m, 2H), 1.22-1.18 (m, 3H)

(ES, m/z): 367 [M + H]⁺ 11.06 (s, 1H), 8.99 (s, 1H), 7.52-7.50 (d, J =7.8 Hz, 1H), 7.40-7.33 (m, 3H), 7.12-7.11 (d, J = 1.5 Hz, 1H), 6.81-6.78(d, J = 9 Hz, 2H), 5.12-5.06 (d, J = 17.4 Hz, 1H), 4.47-4.37 (m, 3H),4.35-4.22 (m, 1H), 1.22-1.20 (d, J = 6 Hz, 3H)

Example 43—Preparation of(S)—N-hydroxy-3-methyl-4-(pyridin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-3-methyl-4-(pyridin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL sealed tube purged and maintained with an inert atmosphereof nitrogen, were placed a solution of methyl(S)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (200mg, 0.90 mmol, 1 equiv) in toluene (3 mL), 2-bromopyridine (529 mg, 3.35mmol, 3 equiv), RuPhos (169 mg, 0.36 mmol, 0.4 equiv), t-BuONa (213 mg,2.22 mmol, 3 equiv) and Pd₂(dba)₃.CHCl₃ (187 mg, 0.18 mmol, 0.2 equiv).The resulting mixture was stirred for 18 h at 120° C. in an oil bath.The solids were filtered out. The filtrate was concentrated undervacuum. The residue was dissolved in EtOAc (20 mL), washed with H₂O(2×20 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated undervacuum. The residue was purified by silica gel chromatography(EtOAc/pet. ether, 1:3) to afford the title compound as a light brownoil (110 mg, 41% yield). MS: (ES, m/z): 299 [M+H]⁺.

Step-2:(S)—N-Hydroxy-3-methyl-4-(pyridin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed a solution of methyl(S)-3-methyl-4-(pyridin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(100 mg, 0.34 mmol, 1 equiv) in THF/MeOH (4:2, 1.5 mL). This wasfollowed by the addition of aq. 1N NaOH (0.67 mL, 2 equiv) and NH₂OH(50% in water, 0.61 mL, 30 equiv) simultaneously. The resulting solutionwas stirred for 2 h at room temperature. The crude product was purifiedby Prep-HPLC (Column: Xbridge Prep C18 OBD, 5 μm, 19×100 mm; MobilePhase A: Water/0.05% formic acid; Mobile Phase B: MeCN; Flow rate: 25mL/min; Gradient: 5% B to 50% B in 6 min; Detector: UV 254, 220 nm) toafford the title compound as a light brown solid (13.3 mg, 13% yield).¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.15 (br s, 1H), 8.10-8.00 (m, 1H),7.90-7.71 (m, 1H), 7.63-7.50 (m, 1H), 7.45-7.35 (m, 1H), 7.23-7.10 (m,1H), 7.09-6.70 (m, 2H), 5.29-5.10 (m, 1H), 4.95-4.74 (m, 2H), 4.59-4.23(m, 2H), 1.30-1.12 (m, 3H). MS: (ES, m/z): 300 [M+H]⁺.

TABLE 21 The following compound was prepared according to the method ofExample 43. Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 300 [M + H]⁺ 11.18 (m, 1H), 8.24-8.23 (d, J = 1.4 Hz, 1H),8.05-8.04 (d, J = 2.6 Hz, 1H), 7.88-7.85 (m, 1H), 7.76-7.73 (m, 1H),7.59-7.57 (d, J = 4.0 Hz, 1H), 7.45-7.33 (m, 1H), 7.16-7.15 (d, J = 0.8Hz, 1H), 5.22-5.18 (d, J = 8.8 Hz, 1H), 4.65-4.61 (d, J = 9.0 Hz, 1H),4.52-4.47 (m, 2H), 4.32-4.25 (m, 1H), 1.25-1.23 (d, J = 2.6 Hz, 3H).

Example 44—Preparation of(S)—N-hydroxy-3-methyl-4-(pyridin-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-3-methyl-4-(pyridin-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 25-mL sealed tube, were placed methyl(S)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (150mg, 0.45 mmol, 1 equiv) in toluene (5 mL), 4-bromopyridine hydrochloride(174 mg, 0.89 mmol, 2 equiv), RuPhos-Pd-G2 (35 mg, 0.05 mmol, 0.1equiv), RuPhos (21 mg, 0.04 mmol, 0.1 equiv) and Cs₂CO₃ (438 mg, 1.34mmol, 3 equiv). The resulting solution was stirred for 18 h at 100° C.in an oil bath. The resulting mixture was concentrated under vacuum. Theresidue was dissolved in EtOAc (50 mL), washed with H₂O (3×30 mL), driedover Na₂SO₄, filtered, and concentrated under vacuum. The residue waspurified by silica gel chromatography (MeOH/CH₂Cl₂, 1:12) to afford thetitle compound as a yellow oil (74.6 mg, 56% yield). MS: (ES, m/z): 299[M+H]⁺.

Step-2:(S)—N-Hydroxy-3-methyl-4-(pyridin-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed a solution of methyl(S)-3-methyl-4-(pyridin-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate)(78 mg, 0.26 mmol, 1 equiv) in THF/MeOH (4:1, 3 mL). This was followedNH₂OH (50% in water, 0.52 mL, 30 equiv) and aq. 1N NaOH (0.52 mL, 2equiv) dropwise with stirring simultaneously. The resulting solution wasstirred for 2 h at room temperature. The crude product was purified byPrep-HPLC (Column: Xbridge Prep C18 OBD, 5 μm, 119×150 mm; Mobile PhaseA: Water/0.05% formic acid; Mobile Phase B: MeCN; Flow rate: 20 mL/min;Gradient: 3% B to 12% B in 8 min; Detector: UV 254, 220 nm) to affordthe title compound as an off-white solid (35.7 mg, 46% yield). ¹H-NMR(400 MHz, DMSO-d₆) δ(ppm): 11.13-11.09 (br s, 1H), 8.04-8.02 (d, J=2.8Hz, 2H), 7.51-7.49 (d, J=4.0 Hz, 1H), 7.33-7.30 (m, 1H), 7.10-7.09 (d,J=0.8 Hz, 1H), 6.65-6.61 (m, 2H), 5.06-5.01 (m, 1H), 4.47-4.31 (m, 3H),4.25-4.21 (m, 1H), 1.16-1.15 (d, J=2.0 Hz, 3H). MS: (ES, m/z): 300[M+H]⁺.

Example 45—Preparation of(S)—N-hydroxy-3-methyl-4-(oxetan-3-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-3-methyl-4-(oxetan-3-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8 mL vial were added methyl(S)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylatehydrochloride (50 mg, 0.194 mmol, 1 equiv) and Et₃N (0.027 mL, 0.194mmol, 1 equiv) and 1,2-dichloroethane (5 mL). This solution was stirredat room temperature for 15 minutes. Next, oxetan-3-one (16.8 mg, 0.233mmol, 1.2 equiv), acetic acid (0.011 mL, 0.194 mmol, 1 equiv), andNaBH(OAc)₃ (103 mg, 0.485 mmol, 2.5 equiv) were added. The resultingsolution was allowed to stir at 50° C. for 16 hours. The reaction waswashed with H₂O (2×5 mL). The organic layer was separated, dried overNa₂SO₄, filtered and concentrated to afford the title compound as awhite solid (65 mg) that was used without further purification. MS: (ES,m/z): 278 [M+H]⁺.

Step-2:(S)—N-Hydroxy-3-methyl-4-(oxetan-3-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 4-mL vial was added methyl(S)-3-methyl-4-(oxetan-3-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(29.6 mg, 0.081 mmol, 1 equiv), NH₂OH (50% in water, 107 μL, 1.62 mmol,20 equiv) and aq. 1N NaOH (324 μL, 0.162 mmol, 4 equiv) in a solution ofTHF/MeOH (4:1, 1.0 mL). The resulting solution was allowed to stir atroom temperature for 16 hours. The reaction was concentrated to drynessand purified by Prep-HPLC (Column: Xbridge Prep C18 OBD, 5 rpm, 19×50mm; Mobile Phase A: Water/0.1% formic acid; Mobile Phase B: MeCN/0.1%formic acid; Flow rate: 23 mL/min; Gradient: 0% B to 35% B in 8 min;Detector: UV 254, 220 nm) to afford the title compound as a light brownoil (34.4 mg, 53% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.16 (s,1H), 9.45 (br s, 1H), 9.02 (s, 1H), 8.60 (d, J=1.2 Hz, 1H), 7.28-7.39(m, 1H), 7.25 (d, J=1.8 Hz, 1H), 7.17 (br d, J=7.6 Hz, 1H), 4.77 (quin,J=6.3 Hz, 1H), 4.32-4.49 (m, 2H), 4.22 (br d, J=15.8 Hz, 1H), 3.76-4.11(m, 2H), 3.34 (s, 6H), 2.94 (s, 2H), 2.78 (s, 2H), 2.37-2.58 (m, 3H),1.86-1.96 (m, 2H), 1.12-1.20 (m, 1H), 1.01-1.25 (m, 3H), 1.01-1.07 (m,1H). MS: (ES, m/z): 279 [M+H]⁺.

Example 46—Preparation of(S)—N-hydroxy-3-methyl-4-(oxetan-3-ylmethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-3-methyl-4-(oxetan-3-ylmethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 100-mL round-bottom flask, were placed methyl(S)-3-methyl-4-(oxetan-3-ylmethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(150 mg, 0.68 mmol, 1 equiv) and acetic acid (5 mL). To this was addedoxetane-3-carbaldehyde (117 mg, 1.36 mmol, 2 equiv). The resultingsolution was stirred for 1.5 h at room temperature. This was followed bythe addition of acetyl ethaneperoxoate sodioboranyl acetate (2.28 g,10.76 mmol, 10 equiv) in several batches. The resulting solution wasstirred for 16 h at room temperature, then concentrated under vacuum.The residue was dissolved in EtOAc (100 mL) and washed with H₂O (4×30mL). The combined organic layers were dried over anhydrous Na₂SO₄,filtered, and concentrated under vacuum. The residue was purified bysilica gel chromatography (MeOH/CH₂Cl₂, 1:20) to afford the titlecompound as a yellow solid (48 mg, 24% yield. MS: (ES, m/z): 292 [M+H]⁺.

Step-2:(S)—N-Hydroxy-3-methyl-4-(oxetan-3-ylmethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, were placed methyl(S)-3-methyl-4-(oxetan-3-ylmethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(60 mg, 0.21 mmol, 1 equiv) and THF/MeOH (4:1, 1.5 mL). Then a solutionof NH₂OH (50% in water, 0.42 mL, 30 equiv) and a solution of sodiumhydroxide (1 mol/L, 0.42 mL, 2 equiv) were added at the same time. Theresulting solution was stirred for 2 h at room temperature. The crudeproduct was purified by Prep-HPLC (Column: Xbridge RP C18 OBD, 5 rpm,19×100 mm; Mobile Phase A: Water/0.05% TFA; Mobile Phase B: MeCN; Flowrate: 25 mL/min; Gradient: 4% B to 58% B in 7 min; Detector: UV 254, 220nm) to afford the title compound as a yellow solid (9 mg, 11% yield).¹H-NMR (400 M Hz, DMSO-d₆) δ(ppm): 11.35 (br s, 1H), 10.30-10.01 (br s,1H), 9.14 (br s, 1H), 7.52-7.24 (m, 3H), 4.65-4.64 (d, J=5.2 hz, 3H),4.51-3.76 (m, 8H), 3.57-3.45 (m, 1H), 1.49-1.15 (m, 3H). MS: (ES, m/z):293 [M+H]⁺.

Example 47—Preparation of(S)—N-hydroxy-4-(4-methoxypiperidine-1-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-4-(4-methoxypiperidine-1-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 25-mL round-bottom flask, was placed a solution of methyl(S)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (100mg, 0.45 mmol, 1 equiv) in CH₂Cl₂ (10 mL), triphosgene (44 mg, 0.16mmol, 0.33 equiv), the resulting solution was stirred for 10 min at 25°C. Then Et₃N (91 mg, 0.90 mmol, 2 equiv) was added into the solution at0° C. and was stirred for 20 min at 25° C. Then a solution of4-methoxypiperidine (208 mg, 1.81 mmol, 4 equiv) in CH₂Cl₂ was added andthe reaction was stirred for 30 min at 25° C. The resulting solution wasdiluted with H₂O (20 mL) and extracted with CH₂Cl₂ (3×15 mL). Thecombined organic layers were dried over anhydrous Na₂SO₄, filtered, andconcentrated under vacuum to afford the title compound as yellow oil(150 mg) which was used without further purification. MS: (ES, m/z): 363[M+H]⁺.

Step-2:(S)—N-Hydroxy-4-(4-methoxypiperidine-1-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 10-mL round-bottom flask, was placed methyl(S)-4-(4-methoxypiperidine-1-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(150 mg, 0.41 mmol, 1 equiv), NH₂OH (50% in water, 1.62 g, 49 mmol, 120equiv), and aq. 1N NaOH (33 mg, 0.83 mmol, 2 equiv). The resultingsolution was stirred for 2 h at 25° C. The crude product was purified byPrep-HPLC (Column: Sunfire Prep C18 OBD, 5 μm, 19×150 mm; Mobile PhaseA: Water/0.05% formic acid; Mobile Phase B: MeCN; Flow rate: 23 mL/min;Gradient: 20% B to 30% B in 8 min; Detector: UV 254, 220 nm) to affordthe title compound as a light pink solid (29.5 mg, 20% yield). ¹H-NMR(300 MHz, DMSO-d₆) δ(ppm): 11.11 (s, 1H), 9.01 (s, 1H), 7.34-7.21 (m,3H), 4.60-4.55 (d, J=17.1 Hz, 1H), 4.32-4.26 (d, J=16.8 Hz, 1H),4.16-4.03 (m, 3H), 3.26-3.21 (m, 6H), 2.81-2.68 (m, 2H), 1.84-1.70 (m,2H), 1.43-1.29 (m, 2H), 1.19 (s, 3H). MS: (ES, m/z): 364[M+H]⁺.

Example 48—Preparation of(S)-4-(azetidine-1-carbonyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-4-(azetidine-1-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into an 8 mL vial were added triphosgene (34.5 mg, 0.116 mmol, 0.4equiv) in CH₂Cl₂ (2 mL). A solution of methyl(S)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylatehydrochloride (75 mg, 0.194 mmol, 1 equiv), Et₃N (0.162 mL, 1.164 mmol,4 equiv) and azetidine hydrochloride (27.2 mg, 0.291 mmol, 1 equiv) inCH₂Cl₂ (2 mL) was added to the stirring solution. This solution wasstirred at room temperature for 16 hours. The reaction was quenched withbrine (2 mL) and concentrated to dryness. The crude product was purifiedby Prep-HPLC (Column: Xbridge Prep C18 OBD, 5 μm, 19×50 mm; Mobile PhaseA: Water/0.1% formic acid; Mobile Phase B: MeCN/0.1% formic acid; Flowrate: 23 mL/min; Gradient: 15% B to 65% B in 8 min; Detector: UV 254,220 nm) to afford the title compound as a white solid (16.3 mg, 18%yield). MS: (ES, m/z): 305 [M+H]⁺.

Step-2:(S)-4-(Azetidine-1-carbonyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 4-mL vial was added methyl(S)-4-(azetidine-1-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(16.3 mg, 0.054 mmol, 1 equiv), NH₂OH (50% in water, 53.1 μL, 1.60 mmol,20 equiv) and aq. 1N NaOH (107 μL, 0.107 mmol, 4 equiv) in a solution ofTHF/MeOH (4:1, 1.0 mL). The resulting solution was allowed to stir atroom temperature for 16 hours. The reaction was concentrated to drynessand was purified by Prep-HPLC (Column: Xbridge Prep C18 OBD, 5 μm, 19×50mm; Mobile Phase A: Water/0.1% formic acid; Mobile Phase B: MeCN/0.1%formic acid; Flow rate: 23 mL/min; Gradient: 0% B to 35% B in 8 min;Detector: UV 254, 220 nm) to afford the title compound. MS: (ES, m/z):306 [M+H]⁺.

TABLE 22 The following compound was prepared according to the method ofExample 48 Structure Found M + H

(ES, m/z): 336 [M + H]⁺

(ES, m/z): 350 [M + H]⁺

(ES, m/z): 343 [M + H]⁺

(ES, m/z): 348 [M + H]⁺

(ES, m/z): 343 [M + H]⁺

(ES, m/z): 350 [M + H]⁺

(ES, m/z): 364 [M + H]⁺

(ES, m/z): 343 [M + H]⁺

(ES, m/z): 362 [M + H]⁺

(ES, m/z): 362 [M + H]⁺

(ES, m/z): 384 [M + H]⁺

Example 49—Preparation of cyclopentyl(S)-8-(hydroxycarbamoyl)-3-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate

Step-1: 4-Cyclopentyl 8-methyl(S)-3-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxylate

Into a 8-mL vial, was placed a solution of methyl(S)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate2,2,2-trifluoroacetate (80 mg, 0.24 mmol, 1 equiv) in CH₂Cl₂ (2.5 mL),Et₃N (96.9 mg, 0.96 mmol, 4 equiv), cyclopentyl chloroformate (53 mg,0.36 mmol, 1.5 equiv). The resulting solution was stirred for 5 h atroom temperature. The residue was concentrated under vacuum and purifiedby silica gel chromatography (EtOAc/pet. ether, 1:1) to afford the titlecompound as a white solid (40 mg, 50% yield). MS: (ES, m/z): 334 [M+H]⁺.

Step-2: Cyclopentyl(S)-8-(hydroxycarbamoyl)-3-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate

Into a 8-mL vial, was placed a solution of 4-cyclopentyl 8-methyl(S)-3-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxylate (40mg, 0.12 mmol, 1 equiv) THF/MeOH (4:1, 2.5 mL). Then aq. 1N NaOH (0.30mL, 2 equiv) and NH₂OH (50% in water, 0.30 mL, 30 equiv) were addedsimultaneously. The resulting solution was stirred for 1 h at roomtemperature. The crude product was purified by Prep-HPLC (Column:Xbridge Prep C18 OBD, m, 19×150 mm; Mobile Phase A: Water/0.1% formicacid; Mobile Phase B: MeCN; Flow rate: 20 mL/min; Gradient: 5% B to 65%B in 8 min; Detector: UV 254, 220 nm) to afford the title compound as awhite solid (11.7 mg, 29% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm):11.13 (s, 1H), 9.02 (s, 1H), 7.31-7.30 (m, 1H), 7.22-7.18 (m, 2H),4.96-4.90 (m, 1H), 4.64-4.60 (m, 1H), 4.50-4.39 (m, 2H), 4.24-4.11 (m,2H), 1.82-1.70 (m, 1H), 1.68-1.55 (m, 5H), 1.32-1.21 (m, 2H), 1.20-1.09(m, 3H). MS: (ES, m/z): 335 [M+H]⁺.

TABLE 23 The following compound was prepared according to the method ofExample 49. Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 349 [M + H]⁺ 11.13 (br s, 1H), 9.01 (br s, 1H), 7.30 (m, 1H),7.24-7.19 (m, 2H), 4.65 (m, 1H), 4.50-4.54 (m, 3H), 4.26-4.12 (m, 2H),1.69-1.60 (m, 3H), 1.42-1.24 (m, 6H), 1.12-1.10 (m, 4H)

(ES, m/z): 295 [M + H]⁺ 11.12 (s, 1H), 9.08-9.02 (s, 1H), 7.32-7.18 (m,3H), 4.64- 4.48 (m, 3H), 4.26-4.11 (m, 2H), 4.04-3.94 (m, 2H), 1.16-0.99 (m, 6H)

(ES, m/z): 361 [M + H]⁺ 11.14 (br s, 1H), 9.08-9.02 (br s, 1H),7.34-7.13 (m, 6H), 6.99-6.95 (m, 1H), 4.89-4.65 (m, 3H), 4.36-4.20 (m,2H), 1.27-1.18 (m, 3H)

(ES, m/z): 309 [M + H]⁺ 11.13 (s, 1H), 8.99 (s, 1H), 7.31-7.18 (m, 3H),4.70-4.47 (m, 4H), 4.25-4.15 (m, 2H), 1.16-0.92 (m, 9H)

Example 50—Preparation of cyclobutyl(S)-8-(hydroxycarbamoyl)-3-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate

Step-1: 4-Cyclobutyl 8-methyl(S)-3-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxylate

Into a 25-mL round-bottom flask, was placed cyclobutanol (65 mg, 0.90mmol, 1 equiv), THF (8 mL), triphosgene (90 mg, 0.33 equiv), and Et₃N(48 mg, 0.47 mmol, 2 equiv). The resulting solution was stirred for 30min at room temperature. Then, methyl(S)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (48mg, 0.22 mmol, 0.24 equiv) was added and the reaction was stirred for 30min at room temperature. The reaction was then quenched by the additionof water (10 mL), extracted with CH₂Cl₂ (3×30 mL), dried over anhydrousNa₂SO₄, filtered, and concentrated under vacuum to afford the titlecompound as brown oil (130 mg, 45% yield). MS: (ES, m/z): 320 [M+H]⁺.

Step-2: Cyclobutyl(S)-8-(hydroxycarbamoyl)-3-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate

Into a 25-mL round-bottom flask, was placed 4-cyclobutyl 8-methyl(S)-3-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxylate(130 mg, 0.41 mmol, 1 equiv), THF/MeOH (4:1, 3 mL), NH₂OH (50% in water,3228 mg, 120 equiv), aq. 1N NaOH (0.82 mL, 2 equiv). The resultingsolution was stirred for 2 h at room temperature. The solids werefiltered out. The crude product was purified by Prep-HPLC (Column:Xbridge Prep C18 OBD, 5 μm, 19×150 mm; Mobile Phase A: Water/10 mmolNH₄HCO₃; Mobile Phase B: MeCN; Flow rate: 23 mL/min; Gradient: 25% B to50% B in 7 min; Detector: UV 254, 220 nm) to afford the title compoundas a white solid (37.1 mg, 28% yield). ¹H-NMR (300 MHz, DMSO-d₆) δ(ppm):7.30-7.18 (m, 3H), 4.80-4.57 (m, 3H), 4.44 (s, 1H), 4.25-4.15 (m, 2H),2.20-2.01 (m, 2H), 1.98-1.92 (m, 1H), 1.67-1.57 (m, 3H), 1.12-1.10 (d,J=6.0 Hz, 3H). MS: (ES, m/z): 321 [M+H]⁺.

TABLE 24 The following compound was prepared according to the method ofExample 50. Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 351 [M + H]⁺ 11.07 (br s, 1H), 9.07 (br s, 1H), 7.31-7.19 (m,3H), 4.70- 4.53 (m, 4H), 4.28-4.17 (m, 2H), 3.74-3.32 (m, 4H), 1.82 (s,2H), 1.53 (s, 2H), 1.21-1.11 (m, 3H)

Example 51—Preparation ofN-hydroxy-4-methyl-4,5-dihydro-2H-spiro[benzo[f][1,4]oxazepine-3,1′-cyclopropane]-8-carboxamide

Step-1: Methyl3-bromo-4-(((1-(hydroxymethyl)cyclopropyl)amino)methyl)benzoate

Into a 500-mL round-bottom flask, was placed(1-aminocyclopropyl)methanol hydrochloride (6 g, 48.55 mmol, 2 equiv),K₂CO₃ (11 g, 79.59 mmol, 3.5 equiv) in MeCN (120 mL), The mixture wasstirred at room temperature for 10 min. This was followed by theaddition of a solution of methyl 3-bromo-4-(bromomethyl)benzoate (15 g,48.71 mmol, 1 equiv) in MeCN (150 mL) dropwise with stirring at 0° C.over 2 h. The resulting solution was stirred overnight at roomtemperature. The resulting mixture was concentrated under vacuum. Theresidue was purified by silica gel chromatography (EtOAc/pet. ether,1:3) to afford the title compound as a yellow oil (7 g, 46% yield). MS:(ES, m/z): 314, 316 [M+H]⁺.

Step-2: Methyl4,5-dihydro-2H-spiro[benzo[f][1,4]oxazepine-3,1′-cyclopropane]-8-carboxylate

Into a 40-mL sealed tube purged and maintained with an inert atmosphereof nitrogen, was placed a solution of methyl3-bromo-4-(((1-(hydroxymethyl)cyclopropyl)amino)methyl)benzoate (1.5 g,4.77 mmol, 1 equiv), CuI (273 mg, 1.43 mmol, 0.3 equiv), K₂CO₃ (992 mg,7.18 mmol, 1.5 equiv) in isopropanol (28 mL). The resulting solution wasstirred overnight at 110° C. in an oil bath. The resulting mixture wasconcentrated under vacuum and the residue was diluted with CH₂Cl₂ (150mL). The solids were filtered out and the filtrate was concentratedunder vacuum. The residue was purified by C18 chromatography(MeCN/H₂O+0.05% TFA, 1:4) to afford the title compound as a yellow solid(0.8 g, 72% yield). MS: (ES, m/z): 234 [M+H]⁺.

Step-3: Methyl4-methyl-4,5-dihydro-2H-spiro[benzo[f][1,4]oxazepine-3,1′-cyclopropane]-8-carboxylate

Into a 25-mL round-bottom flask, was placed methyl4,5-dihydro-2H-spiro[benzo[f][1,4]oxazepine-3,1′-cyclopropane]-8-carboxylate(130 mg, 0.56 mmol, 1 equiv), acetic acid (3 mL), acetal (147 g, 3.35mmol, 6 equiv). The resulting solution was stirred for 2 h at roomtemperature. Then NaBH(OAc)₃ (1.18 g, 5.58 mmol, 10 equiv) was added.The resulting solution was stirred overnight at room temperature. Theresulting mixture was concentrated under vacuum. The residue waspurified by silica gel chromatography (EtOAc/pet. ether, 1:5) to affordthe title compound as a white solid (18.3 mg, 13% yield). MS: (ES, m/z):248 [M+H]⁺.

Step-4:N-Hydroxy-4-methyl-4,5-dihydro-2H-spiro[benzo[f][1,4]oxazepine-3,1′-cyclopropane]-8-carboxamide

Into a 25-mL round-bottom flask, was placed methyl4-methyl-4,5-dihydro-2H-spiro[benzo[f][1,4]oxazepine-3,1′-cyclopropane]-8-carboxylate(18.3 mg, 0.07 mmol, 1 equiv), THF/MeOH (4:1, 1.5 mL), NH₂OH (50% inwater 489 mg, 7.41 mmol, 105 equiv), aq. 1N NaOH (0.15 mL, 2.14 equiv).The resulting solution was stirred for 2.5 h at room temperature. Thecrude product was purified by Prep-HPLC (Column: Xbridge Prep C18 OBD, 5μm; Mobile Phase A: Water/0.05% formic acid; Mobile Phase B: MeCN;Detector: UV 254, 220 nm) to afford the title compound as a pink solid(8.9 mg, 42% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.34 (br s, 1H),9.38-8.98 (br s, 1H), 7.69-7.47 (m, 3H), 4.73-4.59 (m, 2H), 4.39-4.22(m, 1H), 3.73-3.69 (m, 1H), 2.63 (s, 3H), 1.69-1.62 (m, 1H), 1.43-1.32(m, 1H), 1.29-1.17 (m, 1H), 1.04-0.94 (m, 1H). MS: (ES, m/z): 249[M+H]⁺.

TABLE 25 The following compound was prepared according to the method ofExample 51. Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 355 [M + H]⁺ 11.31 (br s, 2H), 7.51-7.33 (m, 5H), 6.92 (d, J= 8.4 Hz, 2H), 4.90-4.17 (m, 4H), 3.77 (m, 5H), 0.82 (s, 4H)

Example 52—Preparation ofN-hydroxy-4-phenyl-4,5-dihydro-2H-spiro[benzo[f][1,4]oxazepine-3,1′-cyclopropane]-8-carboxamide

Step-1: Methyl4-phenyl-4,5-dihydro-2H-spiro[benzo[f][1,4]oxazepine-3,1′-cyclopropane]-8-carboxylate

Into a 50-mL round-bottom flask, was placed Cu(OAc)₂ (100 mg, 0.55 mmol,2.14 equiv), methyl4,5-dihydro-2H-spiro[benzo[f][1,4]oxazepine-3,1′-cyclopropane]-8-carboxylate(60 mg, 0.26 mmol, 1 equiv). phenyl boronic acid (65 mg, 0.53 mmol, 2.05equiv), 4 Å molecular sieves (50 mg), CH₂Cl₂ (15 mL), Et₃N (100 mg, 0.99mmol, 3.84 equiv). The resulting solution was stirred for 48 h at 25° C.The resulting mixture was concentrated under vacuum and then purified bysilica gel chromatography (EtOAc/pet. ether, 1:1) to afford the titlecompound as a yellow solid (31 mg, 39% yield). MS: (ES, m/z): 310[M+H]⁺.

Step-2:N-Hydroxy-4-phenyl-4,5-dihydro-2H-spiro[benzo[f][1,4]oxazepine-3,1′-cyclopropane]-8-carboxamide

Into a 25-mL round-bottom flask, was placed methyl4-phenyl-4,5-dihydro-2H-spiro[benzo[f][1,4]oxazepine-3,1′-cyclopropane]-8-carboxylate(25 mg, 0.08 mmol, 1 equiv), NH₂OH (50% in water, 0.32 g, 4.8 mmol, 60equiv), aq. 1N NaOH (0.16 mL, 2 equiv), THF/MeOH (4:1, 2 mL). Theresulting solution was stirred for 5 h at 25° C. The crude product waspurified by Prep-HPLC. (Column: Xbridge Prep C18 OBD, 5 μm, 19×150 mm;Mobile Phase A: Water/0.05% TFA; Mobile Phase B: MeCN; Flow rate: 20mL/min; Gradient: 30% B to 70% B in 10 min; Detector: UV 254, 220 nm) toafford the title compound as a brown oil (3.1 mg, 12% yield). ¹H-NMR(400 MHz, DMSO-d₆) δ(ppm): 11.13 (br s, 1H), 7.61 (d, J=2 hz, 2H),7.51-7.26 (m, 2H), 7.14-7.03 (m, 4H), 6.64-6.61 (m, 1H), 5.07 (s, 2H),4.42 (s, 2H), 1.23-1.16 (m, 2H), 0.99-0.85 (m, 2H). MS: (ES, m/z): 311[M+H]⁺.

Example 53—Preparation of(S)-3-ethyl-N-hydroxy-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-3-bromo-4-(((1-hydroxybutan-2-yl)amino)methyl)benzoate

Into a 500-mL round-bottom flask, was placed a solution of(2S)-2-aminobutan-1-ol (7 g, 78.53 mmol, 1.8 equiv) in MeCN (150 mL),K₂CO₃ (9 g, 65.22 mmol, 1.5 equiv) and a solution of methyl3-bromo-4-(bromomethyl)benzoate (13.5 g, 43.84 mmol, 1 equiv) in MeCN(100 mL). The resulting mixture was stirred for 14 h at room temperatureand then concentrated under vacuum. The residue was diluted with H₂O(200 mL) and extracted with EtOAc (2×200 mL). The combined organiclayers were washed with H₂O (2×200 mL) and concentrated under vacuum.The residue was purified by silica gel chromatography (EtOAc/pet. ether,1:9) to afford the title compound as an off-white solid (6.9 g, 50%yield). MS: (ES, m/z): 316 [M+H]⁺.

Step-2: Methyl(S)-3-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 150-mL pressure tank reactor purged and maintained with an inertatmosphere of nitrogen, was placed a solution of methyl(S)-3-bromo-4-(((1-hydroxybutan-2-yl)amino)methyl)benzoate (6.9 g, 21.82mmol, 1 equiv) in isopropanol (130 mL), K₂CO₃ (5.14 g, 37.25 mmol, 1.7equiv) and CuI (2.08 g, 10.95 mmol, 0.5 equiv). The resulting mixturewas stirred for 20 h at 110° C. in an oil bath, then was concentratedunder vacuum. The residue was diluted with H₂O (1 mL) and extracted withCH₂Cl₂ (3×100 mL). The combined organic layers were washed with H₂O(3×100 mL) and concentrated under vacuum. The residue was purified bysilica gel chromatography (EtOAc/pet. ether, 1:3) to afford the titlecompound as a green oil (2.1 g), which was used without furtherpurification. MS: (ES, m/z): 236 [M+H]⁺.

Step-3: Methyl(S)-3-ethyl-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, was placed a solution of methyl(S)-3-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (130mg, 0.55 mmol, 1 equiv) in acetic acid (3 mL). This was followed by theaddition of formaldehyde (100 mg, 3.33 mmol, 6 equiv) and the reactionwas stirred for 2 h. To this was added NaBH(OAc)₃ (1.16 g, 5.50 mmol, 10equiv). The resulting solution was stirred for 26 h at room temperatureand concentrated under vacuum. The residue was diluted with H₂O (10 mL),extracted with EtOAc (3×10 mL). The organic combined layers wereconcentrated under vacuum. The residue was purified by silica gelchromatography (EtOAc/pet. ether, 1:3) to afford the title compound as acolorless oil (79 mg, 57% yield). MS: (ES, m/z): 250 [M+H]⁺

Step-4:(S)-3-Ethyl-N-hydroxy-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed a solution of methyl(S)-3-ethyl-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(79 mg, 0.32 mmol, 1 equiv) in THF:MeOH (4:1, 2 mL). This were followedby the addition of NH₂OH (50% in H₂O, 0.63 mL, 30 equiv) and aq. 1N NaOH(0.64 mL, 2 equiv). The resulting solution was stirred for 2 h at roomtemperature. The crude product was purified by Prep-HPLC (Column:Xbridge Prep C18 OBD, 5 μm, 19×250 mm; Mobile Phase A: Water/0.05%formic acid; Mobile Phase B: MeCN; Flow rate: 30 mL/min; Gradient: 15% Bto 40% B in 7 min; Detector: UV 254, 220 nm). Aq. 1N HCl (0.32 mL) wasadded to the product fractions and lyophilized to afford the titlecompound as the HCl salt as a light brown solid (13.9 mg, 15% yield).¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.60 (s, 1H), 11.59-11.21 (m, 1H),7.58-7.42 (m, 3H), 4.78-4.77 (d, J=4.0 Hz, 0.6H), 4.71-4.67 (d, J=16.0Hz, 0.6H), 4.39-4.32 (m, 2.7H), 4.10-4.06 (m, 0.5H), 3.77 (m, 0.5H),3.47-3.46 (m, 0.5H), 2.76-2.75 (m, 1.5H), 2.67-2.51 (m, 1.5H), 2.08-2.00(m, 1H), 1.83-1.80 (m, 0.5H), 1.58-1.56 (m, 0.5H), 1.05-1.01 (m, 3H).MS: (ES, m/z): 251 [M+H]⁺.

Example 54—Preparation of(S)-3-ethyl-N-hydroxy-4-(4-methoxybenzyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-3-ethyl-4-(4-methoxybenzyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, was placed a solution of methyl(S)-3-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (130mg, 0.55 mmol, 1 equiv) in THF (2 mL). This was followed by the additionof sodium hydride (60% dispersion in oil, 68 mg, 3 equiv) at 0° C. in 30min. To this was added 1-(bromomethyl)-4-methoxybenzene (111 mg, 0.55mmol, 1 equiv). The resulting solution was stirred for 20 h at roomtemperature. The reaction was then quenched by the addition of aq. NH₄Clsolution (3 mL), then concentrated under vacuum. The residue was dilutedwith H₂O (10 mL), extracted with EtOAc (3×10 mL), and the combinedorganic layers were concentrated under vacuum. The residue was purifiedby silica gel chromatography (EtOAc/pet. ether, 1:4) to afford the titlecompound as a yellow oil (140 mg). MS: (ES, m/z): 356 [M+H]⁺.

Step-2:(S)-3-Ethyl-N-hydroxy-4-(4-methoxybenzyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed a solution of methyl(S)-3-ethyl-4-(4-methoxybenzyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(140 mg, 0.39 mmol, 1 equiv) in THF:MeOH (4:1, 2 mL). This were followedby the addition of NH₂OH (50% in H₂O, 0.79 mL, 30 equiv) and aq. 1N NaOH(0.79 mL, 2 equiv). The resulting solution was stirred for 2 h at roomtemperature. The crude product was purified by Prep-HPLC (Column:Xbridge Prep C18 OBD, 5 μm, 19×250 mm; Mobile Phase A: Water/0.05%formic acid; Mobile Phase B: MeCN; Flow rate: 30 mL/min; Gradient: 30% Bto 70% B in 10 min; Detector: UV 254, 220 nm). Aq. 1N HCl (0.4 mL) wasadded to the product fractions and lyophilized to afford the titlecompound as the HCl salt as a pink solid (68.7 mg, 44% yield). ¹H-NMR(400 MHz, DMSO-d₆) δ(ppm): 11.34 (s, 1H), 11.02-10.74 (m, 1H), 9.19-9.14(br, 1H), 7.56-7.20 (m, 5H), 7.10-7.02 (m, 2H), 4.80-4.72 (d, J=32 Hz,0.71H), 4.60-4.52 (m, J=32 Hz, 0.76H), 4.51-4.19 (m, 5H), 3.88 (m, 3H),3.50-3.31 (m, 1H), 2.08-1.91 (m, 2H), 1.01-0.92 (m, 3H). MS: (ES, m/z):357 [M+H]⁺.

Example 55—Preparation of(S)-3-ethyl-N-hydroxy-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-3-ethyl-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 8-mL sealed tube purged and maintained with an inert atmosphereof nitrogen, was placed a solution of methyl(S)-3-ethyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (200mg, 0.85 mmol, 1 equiv) in toluene (2.5 mL), iodobenzene (519 mg, 2.54mmol, 3 equiv), Cs₂CO₃ (834 mg, 2.56 mmol, 3 equiv), BINAP (211 mg, 0.34mmol, 0.4 equiv) and Pd(OAc)₂ (38 mg, 0.17 mmol, 0.2 equiv). Theresulting mixture was stirred for 20 h at 110° C. in an oil bath. Theresulting mixture was concentrated under vacuum. The residue was dilutedwith H₂O (10 mL), extracted with EtOAc (3×10 mL), and the combinedorganic layers were concentrated under vacuum. The residue was purifiedby silica gel chromatography (EtOAc/pet. ether, 1:5) to afford the titlecompound as a yellow oil (40 mg, 15% yield). MS: (ES, m/z): 312 [M+H]⁺.

Step-2:(S)-3-Ethyl-N-hydroxy-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed a solution of methyl(S)-3-ethyl-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(40 mg, 0.13 mmol, 1 equiv) in THF/MeOH (4:1, 1.5 mL). This werefollowed by the addition of NH₂OH (50% in H₂O, 0.26 mL, 30 equiv.) andaq. 1N NaOH (0.26 mL, 2 equiv,). The resulting solution was stirred for2 h at room temperature. The crude product was purified by Prep-HPLC(Column: Xbridge Prep C18 OBD, 5 μm, 19×150 mm; Mobile Phase A:Water/0.05% formic acid; Mobile Phase B: MeCN; Flow rate: 30 mL/min;Gradient: 15% B to 60% B in 7 min; Detector: UV 254, 220 nm). Aq. 1N HCl(0.13 mL) was added to the product fractions and lyophilized to affordthe title compound as the HCl salt as an off-white solid (12.2 mg, 27%yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.01 (s, 1H), 7.49-7.47 (d,J=8.0 Hz, 1H), 7.36-7.34 (d, J=8.0 Hz, 1H), 7.09-7.03 (m, 3H), 6.71-6.69(d, J=8.0 Hz, 2H), 6.55-6.53 (d, J=8.0 Hz, 1H), 4.95-4.91 (m, 1H),4.41-4.36 (m, 1H), 4.35-4.29 (m, 2H), 4.13 (m, 1H), 1.67-1.56 (m, 2H),1.01-0.98 (m, 3H). MS: (ES, m/z): 313 [M+H]⁺.

TABLE 26 The following compound was prepared according to the method ofExample 55, using 1-bromo-2-methylbenzene in Step 1. Found Structure M +H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 327 [M + H]⁺ 11.10 (br, 1H), 7.26-7.23 (m, 2H), 7.19-7.17 (m,1H), 7.09- 7.06 (m, 2H), 7.04-7.02 (m, 1H), 6.91-6.89 (m, 1H), 4.55-4.51 (d, J = 16.0 Hz, 1H), 4.38-4.26 (m, 2H), 4.14-4.10 (d, J = 16.0 Hz,1H), 3.54-3.52 (m, 1H), 2.24 (s, 3H), 1.56-1.41 (m, 2H), 0.88-0.84 (m,3H)

Example 56—Preparation of(S)—N-hydroxy-3-(methoxymethyl)-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(R)-3-bromo-4-(((1-hydroxy-3-methoxypropan-2-yl)amino)methyl)benzoate

Into a 500-mL round-bottom flask, was placed(2R)-2-amino-3-methoxypropan-1-ol hydrochloride (6 g, 42.37 mmol, 1.2equiv), a solution of K₂CO₃ (14 g, 101.3 mmol, 2.8 equiv) in MeCN (100mL). This was followed by the addition of a solution of methyl3-bromo-4-(bromomethyl)benzoate (11 g, 35.72 mmol, 1 equiv) in MeCN (100mL) dropwise with stirring at 0° C. The resulting solution was stirredovernight at room temperature, then concentrated under vacuum. Theresidue was purified by silica gel chromatography (EtOAc/pet. ether,1:1) to afford the title compound as a yellow solid (4.5 g, 38% yield).MS: (ES, m/z): 332, 334 [M+H]⁺.

Step-2: Methyl(S)-3-(methoxymethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 150-mL sealed tube, was placed a solution of methyl(R)-3-bromo-4-(((1-hydroxy-3-methoxypropan-2-yl)amino)methyl)benzoate(4.5 g, 13.55 mmol, 1 equiv) in isopropanol (120 mL), K₂CO₃ (2.813 g,20.21 mmol, 1.5 equiv), and CuI (0.76 g, 3.99 mmol, 0.3 equiv). Theresulting mixture was stirred overnight at 110° C. in an oil bath, thenconcentrated under vacuum. The residue was purified by silica gelchromatography (EtOAc/pet. ether, 1:1) to afford the title compound as ayellow oil (550 mg, 16% yield). MS: (ES, m/z): 252 [M+H]⁺.

Step-3: Methyl(S)-3-(methoxymethyl)-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 25-mL round-bottom flask, was placed methyl(S)-3-(methoxymethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(200 mg, 0.80 mmol, 1 equiv), acetic acid (5 mL), acetal (175.2 mg, 4mmol, 5 equiv). The resulting solution was stirred for 2 h at roomtemperature. This was followed by the addition of NaBH(OAc)₃ (1182.5 mg,5.58 mmol, 7 equiv). The resulting mixture was stirred overnight at roomtemperature. Then the solids were filtered out and the filtrate wasconcentrated under vacuum. The residue was purified by silica gelchromatography (EtOAc/pet. ether, 1:1) to afford the title compound as acolorless oil (60.2 mg, 29% yield). MS: (ES, m/z): 266 [M+H]⁺.

Step-4:(S)—N-Hydroxy-3-(methoxymethyl)-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 25-mL round-bottom flask, was placed methyl(S)-3-(methoxymethyl)-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(60.2 mg, 0.23 mmol, 1 equiv), THF/MeOH (4:1, 1.2 mL), NH₂OH (50% inwater, 1499 mg, 22.72 mmol, 100 equiv), aq. 1N NaOH (0.45 mL, 2 equiv).The resulting solution was stirred for 1 h at room temperature. Thecrude product was purified by Prep-HPLC (Column: Xbridge Prep C18 OBD, 5μm, 19×150 mm; Mobile Phase A: Water/0.05% TFA; Mobile Phase B: MeCN;Detector: UV 254, 220 nm) to afford the title compound as a yellow solid(22 mg, 32% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.55-10.78 (m,2H), 7.62-7.41 (m, 3H), 4.74-4.70 (d, J=16 Hz, 1H), 4.58-4.27 (m, 3H),4.14-4.11 (m, 1H), 3.99-3.91 (m, 1H), 3.90-3.81 (m, 1H), 3.78-3.63 (m,1H), 3.37-3.33 (d, J=16 Hz, 3H), 2.84 (s, 2H), 2.58 (s, 1H). MS: (ES,m/z): 267 [M+H]⁺.

TABLE 27 The following compounds were prepared according to the methodof Example 56, using (2S)-2-amino-3-methoxypropan-1-ol hydrochloride inStep 1 where appropriate. Found Structure M + H ¹H-NMR (400 MHz,DMSO-d₆) δ(ppm)

(ES, m/z): 267 [M + H]⁺ 11.49-10.83 (m, 2H), 9.20 (br s, 1H), 7.6-7.34(m, 3H), 4.73- 3.43 (m, 10H), 2.96-2.84 (m, 3H)

(ES, m/z): 373 [M + H]⁺ 11.82-11.16 (m, 2H), 7.56-7.44 (m, 5H),6.99-6.97 (d, J = 6 Hz, 2H), 4.81-4.77 (m, 1H), 4.57-4.53 (m, 1H),4.70-4.36 (m, 3H), 4.24 (m, 2H), 4.01 (m, 1H), 3.88-3.83 (m, 1H), 3.77(s, 3H), 3.56 (s, 1H), 3.32-3.28 (m, 2H)

(ES, m/z): 373 [M + H]⁺ 11.45-11.08 (m, 1H), 10.71-10.53 (m, 1H),9.58-8.69 (br s, 1H), 7.61-7.12 (m, 5H), 7.04-3.93 (m, 2H), 4.91-3.98(m, 7H), 3.97-3.68 (m, 5H), 3.33-3.24 (s, 3H)

Example 57—Preparation of(S)—N-hydroxy-3-(methoxymethyl)-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-3-(methoxymethyl)-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 50-mL round-bottom flask, was placed methyl(S)-3-(methoxymethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(200 mg, 0.80 mmol, 1 equiv), a solution of phenylboronic acid (291 mg,2.39 mmol, 3 equiv) in CH₂Cl₂ (5 mL), 4 Å molecular sieve (60 mg), Et₃N(241 mg, 2.38 mmol, 3 equiv) and Cu(OAc)₂ (144 mg, 0.79 mmol, 1 equiv).The resulting solution was stirred overnight at room temperature. Thereaction was then quenched by the addition of H₂O (10 mL) and extractedwith CH₂Cl₂ (3×50 mL). The combined organic layers were concentratedunder vacuum. The residue was purified by silica gel chromatography(EtOAc/pet. ether, 1:10) to afford the title compound as a yellow solid(33 mg, 12% yield). MS: (ES, m/z): 328 [M+H]⁺.

Step-2:(S)—N-Hydroxy-3-(methoxymethyl)-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 50-mL round-bottom flask, was placed a solution of methyl(S)-3-(methoxymethyl)-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(33 mg, 0.10 mmol, 1 equiv) in THF/MeOH (4:1, 2.5 mL), NH₂OH (50% inwater, 0.42 mL, 60 equiv), aq. 1N NaOH (0.2 mL, 2 equiv). The resultingsolution was stirred for 3 h at room temperature. The crude product waspurified by Prep-HPLC (Column: Xbridge Prep C18 OBD, 5 μm, 19×150 mm;Mobile Phase A: Water/0.05% formic acid; Mobile Phase B: MeCN; Flowrate: 25 mL/min; Gradient: 30% B to 70% B in 10 min; Detector: UV 254,220 nm). Aq. 1N HCl (0.1 mL) was added to the product fractions andlyophilized to afford the title compound as the HCl salt as a yellowsolid (8.5 mg, 23% yield). ¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 11.20 (brs, 1H), 7.48-7.46 (d, J=6 Hz, 1H), 7.35-7.32 (d, J=9 Hz, 1H), 7.10-7.03(m, 3H), 6.70-6.67 (d, J=9 Hz, 2H), 6.58-6.54 (m, 1H), 5.09-5.03 (d,J=18 Hz, 1H), 4.51-4.27 (m, 4H), 3.59-3.57 (d, J=6 Hz, 2H), 3.33 (s,3H). MS: (ES, m/z): 329 [M+H]⁺.

TABLE 28 The following compounds were prepared according to the methodof Example 57, using (2S)-2-amino-3-methoxypropan-1-ol hydrochloride inStep 1 where appropriate. Found Structure M + H ¹H-NMR (400 MHz,DMSO-d₆) δ(ppm)

(ES, m/z): 329 [M + H]⁺ 11.18-11.05 (br s, 1H), 7.49-7.47 (d, J = 8 Hz,1H), 7.35- 7.33 (d, J = 8 Hz, 1H), 7.11-7.04 (m, 3H), 6.70-6.68 (d, J =8 Hz, 2H), 6.59-6.52 (m, 1H), 5.09-5.05 (d, J = 16 Hz, 1H), 4.55-4.46(m, 1H), 4.41-4.22 (m, 3H), 3.59-3.58 (d, J = 4 Hz, 2H), 3.33 (s, 3H)

(ES, m/z): 343 [M + H]⁺ 11.13 (br s, 1H), 9.60 (br s, 1H), 7.27-7.20 (m,3H), 7.17- 7.07 (m, 3H), 6.97-6.93 (m, 1H), 4.46-4.41 (m, 3H), 4.26-4.22 (d, J = 16 Hz, 1H), 3.80-3.77 (m, 1H), 3.51-3.41 (m, 1H), 3.31-3.27(m, 1H), 3.22 (s, 3H), 2.17 (s, 3H).

(ES, m/z): 343 [M + H]⁺ 11.23 (br s, 1H), 7.20-7.27 (m, 3H), 7.07-7.17(m, 3H), 6.93-6.97 (t, J = 7.2 hz, 1H), 4.41-4.46 (m, 3H), 4.22-4.26 (d,J = 16.4 Hz, 1H), 3.77-3.80 (m, 1H), 3.47-3.51 (t, J = 8.8 Hz, 1H),3.27-3.31 (m, 1H), 3.22 (s, 3H), 2.17 (s, 3H)

Example 58—Preparation of(S)-3-benzyl-N-hydroxy-4-(morpholine-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-3-bromo-4-(((1-hydroxy-3-phenylpropan-2-yl)amino)methyl)benzoate

Into a 40-mL scintillation vial was placed(S)-2-amino-3-phenylpropan-1-ol (271 mg, 1.79 mmol, 1.30 equiv), K₂CO₃(572 mg, 4.14 mmol, 3.00 equiv) and MeCN (15 ml). The resulting slurrywas cooled to 0° C. in an ice-water bath. Next, a solution of methyl3-bromo-4-(bromomethyl)benzoate (425 mg, 1.380 mmol, 1.00 equiv) in MeCN(3 mL) was added dropwise over 10 min while maintaining the internaltemperature at 0° C. The ice bath was removed and the resulting slurrywas allowed to slowly warm to room temperature. Stirring continued atroom temperature for 16 h. The reaction was concentrated under reducedpressure to remove most of the MeCN. The concentrated mixture waspartitioned between EtOAc (10 mL) and H₂O (5 ml). The organic phase waswashed with brine (5 mL), dried over Na₂SO₄, filtered and concentratedto afford the title compound as a yellow oil (628 mg), which was usedwithout further purification. MS: (ES, m/z): 379 [M+H]⁺.

Step-2: Methyl(S)-3-benzyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 40-mL scintillation vial was placed methyl(S)-3-bromo-4-(((1-hydroxy-3-phenylpropan-2-yl)amino)methyl)benzoatehydrochloride (522 mg, 1.39 mmol, 1 equiv) in isopropanol (5 mL). K₂CO₃(381 mg, 2.76 mmol, 2 equiv) was added followed by CuI (52.6 mg, 0.276mmol, 0.2 equiv). The resulting solution was heated to reflux for 18 h.The resulting mixture was filtered through a celite pad and washed withisopropanol (10 mL). The filtrate was reduced in volume to −5 mL and 10NHCl (1.1 equiv) was added dropwise, with stirring, to the filtrate. Theresulting slurry was cooled in an ice bath for 30 min before beingfiltered to afford the title compound as the HCl salt as a yellow solid(252 mg, 49.3% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 7.68-7.77 (m,1H), 7.58-7.66 (m, 1H), 7.54 (d, J=1.8 Hz, 1H), 7.23-7.45 (m, 4H),4.36-4.58 (m, 2H), 4.26 (br d, J=11.4 Hz, 1H), 3.74-4.05 (m, 4H), 3.42(s, 1H), 3.07-3.27 (m, 2H), 2.90 (br dd, J=13.6, 9.2 Hz, 1H), 1.03 (d,J=6.2 Hz, 1H). MS: (ES, m/z): 298 [M+H]⁺.

Step-3: Methyl(S)-3-benzyl-4-(morpholine-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 4-mL vial equipped with a stir bar was placed a solution oftriphosgene (17.8 mg, 0.060 mmol, 0.4 equiv) in CH₂Cl₂ (2 mL). Next, asolution of methyl(S)-3-benzyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylatehydrochloride (50 mg, 0.150 mmol, 1 equiv), Et₃N (0.063 mL, 0.449 mmol,3 equiv), and morpholine (13.5 mg, 0.150 mmol, 1 equiv) and CH₂Cl₂ (2mL) was added. The resulting solution was stirred at room temperaturefor 16 h. The reaction was concentrated to dryness to afford the titlecompound (61.4 mg) which was used without further purification. MS: (ES,m/z): 410 [M+H]⁺.

Step-3:(S)-3-Benzyl-N-hydroxy-4-(morpholine-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 4-mL vial was placed methyl(S)-3-benzyl-4-(morpholine-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(61.6 mg, 0.150 mmol, 1 equiv), NH₂OH (50% in water, 0.1 mL, 1.5 mmol,10 equiv), and aq. 1N NaOH (0.3 mL, 0.3 mmol, 2 equiv) in a solution ofTHF/MeOH (4:1, 2.0 mL). The resulting solution was stirred at roomtemperature for 2 h, then concentrated. The residue was purified byPrep-HPLC (Column: Xbridge Prep C18 OBD, 5 μm, 19×50 mm; Mobile Phase A:Water/0.1% formic acid; Mobile Phase B: MeCN/0.1% formic acid; Flowrate: 23 mL/min; Gradient: 15% B to 65% B in 8 min; Detector: UV 254,220 nm) to afford the title compound as a white solid (4.5 mg, 11%yield). MS: (ES, m/z): 412 [M+H]⁺.

Example 59—Preparation of(R)—N-hydroxy-4-(4-methoxybenzyl)-5-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: tert-Butyl (2-(2-acetyl-5-bromophenoxy)ethyl)carbamate

Into a 500-mL 3-necked round-bottom flask, was placed1-(4-bromo-2-hydroxyphenyl)ethan-1-one (30 g, 139 mmol, 1 equiv) in DMF(150 mL), K₂CO₃ (29 g, 209 mmol, 1.5 equiv), potassium iodide (23.2 g, 1equiv) and tert-butyl N-(2-bromoethyl)carbamate (47 g, 209 mmol, 1.5equiv). The resulting mixture was stirred overnight at 50° C. The solidswere filtered out. The filtrate was quenched with of H₂O (50 mL) andextracted with EtOAc (5×100 mL). The combined organic layers were washedwith brine (3×50 mL), dried over anhydrous Na₂SO₄, filtered, andconcentrated under vacuum. The residue was triturated with a solution ofEtOAc/pet. ether (1:10, 100 mL) to afford the title compound as anoff-white solid (42 g, 84% yield). MS: (ES, m/z): 358 [M+H]⁺.

Step-2: 8-Bromo-5-methyl-2,3-dihydrobenzo[f][1,4]oxazepine

Into a 500-mL round-bottom flask, was placed tert-butyl2-(2-acetyl-5-bromophenoxy)ethylcarbamate (23 g, 64.20 mmol, 1 equiv) inCH₂Cl₂ (100 mL) and TFA (25 mL). The resulting solution was stirredovernight at room temperature, then concentrated under vacuum to affordthe title compound as a yellow solid (15.4 g), which was used withoutfurther purification. MS: (ES, m/z): 240 [M+H]⁺.

Step-3: 8-Bromo-5-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine

Into a 500-mL round-bottom flask, was placed a solution of8-bromo-5-methyl-2,3-dihydrobenzo[f][1,4]oxazepine (15.4 g, 64.14 mmol,1 equiv) in MeOH (200 mL). The pH value of the solution was adjusted to7 with anhydrous NaOAc at 0° C. Then Na(CN)BH₃ (18.1 g, 288 mmol, 4.5equiv) was added at 0° C. The resulting mixture was stirred for 4 h atroom temperature and concentrated under vacuum. H₂O (50 mL) was added tothe residue and the solids were collected by filtration to afford thetitle compound as a white solid (15 g). MS: (ES, m/z): 242 [M+H]⁺.

Step-4: tert-Butyl8-bromo-5-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate

Into a 500-mL round-bottom flask, was placed tert-butyl8-bromo-5-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate (9g, 37.17 mmol, 1 equiv) in CH₂Cl₂ (80 mL), Et₃N (11.25 g, 111 mmol, 3equiv) and di-tert-butyl dicarbonate (12.1 g, 55.44 mmol, 1.5 equiv).The resulting solution was stirred overnight at room temperature, thenconcentrated under vacuum. The crude product was purified byFlash-Prep-HPLC (Column: silica gel; Mobile Phase A: pet. ether, MobilePhase B: EtOAc; Gradient: 0% B to 10% B in 50 min; Detector: 254 nm) toafford the title compound as white solid (11 g, 86% yield). MS: (ES,m/z): 342 [M+H]⁺.

Step-5: 4-(tert-Butyl) 8-ethyl(R)-5-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxylate and4-(tert-butyl) 8-ethyl(S)-5-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxylate

Into a 50-mL sealed tube, was placed tert-butyl8-bromo-5-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate((2.5 g, 7.33 mmol, 1 equiv) in EtOH (25 mL), Et₃N (2.22 g, 22 mmol, 3equiv) and Pd(dppf)Cl₂ (0.534 g, 0.73 mmol, 0.1 equiv). To the abovereaction mixture CO (g) (60 atm) was introduced. The resulting mixturewas stirred overnight at 120° C., then concentrated under vacuum. Thecrude product was purified by Flash-Prep-HPLC (Column: silica gel;Mobile Phase A: pet. ether, Mobile Phase B: EtOAc; Gradient: 0% B to 10%B in 30 min; Detector: 254 nm) to afford the title compounds as aracemic mixture. The racemate was then purified by Prep-SFC (Column:(R,R) WHELK-01 Kromasil, 10 μm, 21.1×250 mm; Mobile Phase A: 75% CO₂,25% isopropanol (0.2% N,N-diethylaniline); Flow rate: 45 mL/min;Detector: UV 254 nm) to afford the single isomers as a light yellow oil(first eluting isomer: 540 mg, 21.9% yield; second eluting isomer: 680mg, 27.7% yield). MS: (ES, m/z): 336 [M+H]⁺.

Step-6: Ethyl(R)-5-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 25-mL round-bottom flask, was placed the first eluting isomerfrom Step 5 (4-(tert-butyl) 8-ethyl(R)-5-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxylate)(540 mg, 1.61 mmol, 1 equiv), CH₂Cl₂ (5 mL), and TFA (2 mL). Theresulting solution was stirred overnight at room temperature, thenconcentrated under vacuum. The crude product was purified byFlash-Prep-HPLC (Column: C18 silica gel; Mobile Phase A: H₂O/0.05% TFA,Mobile Phase B: MeCN; Gradient: 5% B to 50% B in 30 min; Detector: 254nm) to afford the title compound as a white solid (450 mg), which wasused without further purification. MS: (ES, m/z): 236 [M+H]⁺.

Step-7: Ethyl(R)-4-(4-methoxybenzyl)-5-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Into a 25-mL round-bottom flask, was placed ethyl(R)-5-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (100mg, 0.43 mmol, 1 equiv) and 4-methoxybenzaldehyde (57 mg, 0.42 mmol, 1equiv) in MeOH (2 mL). After stirring for 30 min, Na(CN)BH₃ (80 mg, 1.27mmol, 3 equiv) was added at 0° C. The resulting solution was stirredovernight at room temperature. The reaction was then quenched by theaddition of H₂O (2 mL) and extracted with CH₂Cl₂ (5×10 mL). The combinedorganic layers were dried over anhydrous Na₂SO₄, filtered, andconcentrated under vacuum. The residue was purified by silica gelchromatography (EtOAc/pet. ether, 1:3) to afford the title compound as ayellow oil (50 mg, 34% yield). MS: (ES, m/z): 356 [M+H]⁺.

Step-8:(R)—N-Hydroxy-4-(4-methoxybenzyl)-5-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Into a 25-mL round-bottom flask, was placed ethyl(R)-4-(4-methoxybenzyl)-5-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(50 mg, 0.14 mmol, 1 equiv), THF/MeOH (4/1, 2 mL), NH₂OH (50% in water,579 mg, 60 equiv), aq. 1N NaOH (0.28 mL, 2 equiv). The resultingsolution was stirred for 8 h at room temperature. The mixture waspurified by Prep-HPLC (Column: Sunfire C18 OBD, 5 μm, 19×150 mm; MobilePhase A: Water/0.05% formic acid; Mobile Phase B: MeCN; Flow rate: 0.7mL/min; Gradient: 5% B to 20% B in 7 min; Detector: UV 254 nm) to affordthe title compound as a brown solid (36 mg, 75% yield). ¹H-NMR (DMSO,400 MHz) δ(ppm): 11.41-10.87 (m, 2H), 9.17 (br s, 1H,), 7.59-7.33 (m,5H), 7.04-6.98 (m, 2H), 4.73 (s, 1H), 4.49-4.34 (m, 3H), 4.13-4.11 (m,1H), 3.86-3.78 (m, 4H), 3.36-3.09 (m, 1H), 1.70-1.67 (m, 3H). MS: (ES,m/z): 343 [M+H].

TABLE 29 The following compound was prepared according to the method ofExample 59, using the second eluting isomer of the Step 5 product. FoundStructure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 343 [M + H]⁺ 11.33-10.60 (m, 2H), 9.17-9.14 (m, 1H),7.54-6.88 (m, 7H), 4.74-4.34 (m, 3H), 4.11-3.44 (m, 6H), 3.13-2.76 (m,1H), 1.69-1.42 (m, 3H)

Example 60—Preparation of(R)—N-hydroxy-4-(4-methoxybenzyl)-5-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carboxamide

Step-1: tert-Butyl (2-(2-acetyl-4-bromophenoxy)ethyl)carbamate

Into a 500-mL 3-necked round-bottom flask, was placed a solution of1-(5-bromo-2-hydroxyphenyl)ethan-1-one (30 g, 139.51 mmol, 1 equiv),K₂CO₃ (29 g, 209.83 mmol, 3 equiv), potassium iodide (23.2 g, 1 equiv)and tert-butyl N-(2-bromoethyl)carbamate (37.5 g, 167.34 mmol, 1.2equiv) in DMF (150 mL). The resulting solution was stirred overnight at50° C. in an oil bath. The reaction mixture was cooled to 0° C. andquenched with H₂O (50 mL). The resulting solution was extracted withCH₂Cl₂ (2×100 mL), washed with brine (5×100 mL) and dried over anhydrousNa₂SO₄. The solids were filtered out and the filtrate was concentratedunder vacuum. The crude product was purified by silica gelchromatography (Gradient 0-50% EtOAc/pet. ether over 50 min) to affordthe title compound as a light yellow solid (39 g, 78% yield). MS: (ES,m/z): 358 [M+H]⁺.

Step-2: 7-Bromo-5-methyl-2,3-dihydrobenzo[f][1,4]oxazepine

Into a 500-mL round-bottom flask, was placed tert-butylN-[2-(2-acetyl-4-bromophenoxy)ethyl]carbamate (20 g, 55.83 mmol, 1equiv), CH₂Cl₂ (100 mL) and TFA (20 mL). The resulting solution wasstirred overnight at room temperature. The resulting mixture wasconcentrated under vacuum to afford the title compound as a red solid(20 g) which was used without further purification. MS: (ES, m/z): 240[M+H]⁺.

Step-3: 7-Bromo-5-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine

Into a 500-mL round-bottom flask, was placed a solution of7-bromo-5-methyl-2,3-dihydrobenzo[f][1,4]oxazepine (10 g, 38.74 mmol, 1equiv) in MeOH (100 mL), the pH value of the solution was adjusted to 7with anhydrous sodium acetate at 0° C. Then Na(CN)BH₃ (7.9 g, 113.52mmol, 3 equiv) was added at 0° C. The resulting solution was stirred for2 h at room temperature. The resulting mixture was concentrated undervacuum and 20 mL of water was added. The solids were collected byfiltration to afford the title compound as a white solid (7 g, 75%yield) which was used without further purification. MS: (ES, m/z): 242[M+H]⁺.

Step-4: tert-Butyl7-bromo-5-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-4-carboxylate

Into a 50-mL round-bottom flask, was placed7-bromo-5-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine (2 g, 8.26 mmol, 1equiv), CH₂Cl₂ (20 mL), Et₃N (2.51 g, 24.80 mmol, 3 equiv),di-tert-butyl dicarbonate (2.71 g, 12.42 mmol, 1.5 equiv). The resultingsolution was stirred overnight at room temperature. The resultingmixture was concentrated under vacuum. The crude product was purified bysilica gel chromatography (Gradient 0-30% EtOAc/pet. ether over 20 min)to afford the title compound as a light yellow oil (2.4 g, 85% yield).MS: (ES, m/z): 342 [M+H]⁺.

Step-5: 4-(tert-Butyl) 7-ethyl(R)-5-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,7(5H)-dicarboxylate

Into a 50-mL pressure tank reactor, was placed tert-butyl7-bromo-5-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-4-carboxylate (2.4g, 7.01 mmol, 1 equiv), ethanol (40 mL), Et₃N (2.1 g, 20.75 mmol, 3equiv), and Pd(dppf)Cl₂ (515.1 mg, 0.70 mmol, 0.1 equiv). CO (g) (60atm) was introduced and the resulting solution was stirred overnight at120° C. The solids were filtered out and the filtrate was concentratedunder vacuum and purified by silica gel chromatography (Gradient 0-10%EtOAc/pet. ether over 30 min) to afford the racemic mixture of the titlecompounds, which were separated by Prep-SFC (Column Chiralpak IC OBD, 5μm, 5×250 mm; Mobile Phase: 75% CO₂, 25% Isopropanol; Flow rate: 170mL/min; Detector, UV 254, 220 nm) to afford the single isomers of thetitle compounds as light yellow oils (first eluting isomer: 440 mg, 19%yield; second eluting isomer: 500 mg, 21% yield). MS: (ES, m/z): 336[M+H]⁺.

Step-6: Ethyl(R)-5-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carboxylate

Into a 50-mL round-bottom flask, was placed the first eluting isomerfrom Step 5 (4-(tert-butyl) 7-ethyl(R)-5-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,7(5H)-dicarboxylate)(440 mg, 1.31 mmol, 1 equiv), CH₂Cl₂ (5 mL), and TFA (2 mL). Theresulting solution was stirred overnight at room temperature andconcentrated under vacuum. The crude product was purified by silica gelchromatography (Gradient 10-50% EtOAc/pet. ether over 30 min) to affordthe title compound as a light yellow oil (300 mg, 97% yield). MS: (ES,m/z): 236 [M+H]⁺.

Step-7: Ethyl(R)-4-(4-methoxybenzyl)-5-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carboxylate

Into a 50-mL round-bottom flask, was placed 4-methoxybenzaldehyde (57.8mg, 0.42 mmol, 1 equiv), MeOH (2 mL), and ethyl(R)-5-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carboxylate (100mg, 0.43 mmol, 1 equiv). The mixture was stirred for 30 min at roomtemperature, and then Na(CN)BH₃ (80.4 mg, 1.28 mmol, 3 equiv) was addedat 0° C. The resulting solution was stirred overnight at roomtemperature. The reaction was then quenched with H₂O (2 mL) andextracted with CH₂Cl₂ (5×10 mL). The combined organic layers were anddried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum.The residue was purified by silica gel chromatography (EtOAc/pet. ether,1:3) to afford the title compounds as a light yellow oil (80 mg, 53%yield). MS: (ES, m/z): 356 [M+H]⁺.

Step-8:(R)—N-Hydroxy-4-(4-methoxybenzyl)-5-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carboxamide

Into a 25-mL round-bottom flask, was placed ethyl(R)-4-(4-methoxybenzyl)-5-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carboxylate(80 mg, 0.23 mmol, 1 equiv), THF/MeOH (1.5 mL, 4:1). This was followedby the addition of NH₂OH (50% in water, 913 mg, 60 equiv) and aq. 1NNaOH (0.46 mL, 2 equiv). The resulting solution was stirred for 2 daysat room temperature. The crude product was purified by Prep-HPLC(Column: Atlantis T3 C18 OBD, 5 μm, 19×150 mm; Mobile Phase A:Water/0.05% TFA; Mobile Phase B: MeCN; Flow rate: 25 mL/min; Gradient:10% B to 40% B in 10 min; Detector, UV 254, 220 nm) to afford the titlecompound as an off-white solid (12 mg, 11% yield). ¹H-NMR (400 MHz,DMSO-d₆) δ(ppm): 11.24 (s, 1H), 10.20-10.13 (br s, 1H), 9.13-9.09 (br s,1H), 7.83-7.76 (br s, 2H), 7.49-7.41 (m, 2H), 7.24-7 (m, 3H), 4.84-4.69(m, 1H), 4.60-3.79 (m, 5H), 3.79 (s, 3H), 3.40-3 (m, 1H), 1.69-1.55 (m,3H). MS: (ES, m/z): 343 [M+H]⁺.

TABLE 30 The following compounds were prepared according to the methodof Example 60, using the second eluting isomer of the Step 5 product.Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 343 [M + H]⁺ 11.24 (s, 1H), 10.23-10.12 (br s, 1H), 9.13-9.04(br s, 1H), 7.76 (s, 2H), 7.50-7.42 (m, 2H), 7.17-7.04 (m, 3H), 4.83(br, 1H), 4.48-4 (m, 5H), 3.78 (s, 3H), 3.34- 3.05 (m, 1H), 1.68-1.53(m, 3H)

Example 61—Preparation ofN8-hydroxy-N4-(4-methoxyphenyl)-2,3-dihydropyrido[2,3-f][1,4]oxazepine-4,8(5H)-dicarboxamide

Step-1: Methyl 5-bromo-6-iodopyridine-3-carboxylate

Into a 1000-mL round-bottom flask, was placed methyl5-bromo-6-chloropyridine-3-carboxylate (11 g, 43.92 mmol, 1 equiv), MeCN(330 mL), trimethylsilyl iodide (8.767 g, 1 equiv) and sodium iodide(19.7 g, 3 equiv). The resulting mixture was stirred for 4 h at 25° C.and then concentrated. The residue was diluted with H₂O (300 mL). The pHvalue of the solution was adjusted to 7 with 2N NaOH. The solids werecollected by filtration to afford the title compound as a yellow solid(16 g) which was used without further purification. MS: (ES, m/z): 250[M+H]⁺.

Step-2: Methyl 5-bromo-6-methylpyridine-3-carboxylate

Into a 250-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed methyl5-bromo-6-iodopyridine-3-carboxylate (6 g, 17.55 mmol, 1 equiv),1,4-dioxane (60 mL), trimethyl-1,3,5,2,4,6-trioxatriborinane (15 mL, 50%in THF, 3 equiv), Pd(dppf)Cl₂.CH₂Cl₂ (1.44 g, 0.1 equiv) and potassiumcarbonate (7.34 g, 53.10 mmol, 3 equiv). The resulting solution wasstirred for 72 h at 75° C. in an oil bath. The reaction mixture wascooled to room temperature. The solids were filtered out. The filtratewas diluted with EtOAc (100 mL), washed with brine (3×30 mL), dried overanhydrous Na₂SO₄, filtered, and concentrated. The residue was purifiedby silica gel chromatography (EtOAc/pet. ether, 1:10) to afford thetitle compound as an off-white solid (3 g, 74% yield). MS: (ES, m/z):230 [M+H]⁺.

Step-3: Methyl 5-bromo-6-(bromomethyl)pyridine-3-carboxylate

Into a 250-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed methyl5-bromo-6-methylpyridine-3-carboxylate (3 g, 13.04 mmol, 1 equiv), CCl₄(60 mL), NBS (2.435 g, 13.68 mmol, 1.05 equiv) and benzoyl peroxide (158mg, 0.62 mmol, 0.05 equiv). The resulting mixture was stirred for 16 hat 80° C. in an oil bath. The reaction mixture was cooled to roomtemperature. The solids were filtered out. The filtrate was concentratedand diluted with EtOAc (150 mL), washed with brine (3×50 mL). Theorganic phase was dried over anhydrous Na₂SO₄, filtered, andconcentrated to afford the title compound as a brown oil (2.5 g) whichwas used without further purification. MS: (ES, m/z): 310 [M+H]⁺.

Step-4: Methyl5-bromo-6-[[(2-hydroxyethyl)amino]methyl]pyridine-3-carboxylate

Into a 250-mL round-bottom flask, was placed MeCN (50 mL),2-aminoethan-1-ol (990 mg, 16.21 mmol, 2 equiv) and potassium carbonate(2.26 g, 16.32 mmol, 2 equiv). This was followed by the addition of asolution of methyl 5-bromo-6-(bromomethyl)pyridine-3-carboxylate (2.5 g,4.86 mmol, 1 equiv) in MeCN (20 mL) dropwise with stirring at 0° C. Theresulting solution was stirred for additional 2 h at 0° C. The solidswere filtered out. The filtrate was concentrated. The residue waspurified by silica gel chromatography (CH₂Cl₂/MeOH, 20:1) to afford thetitle compound as a yellow solid (0.7 g, 50% yield). MS: (ES, m/z): 289[M+H]⁺.

Step-5: Methyl5-bromo-6-(((tert-butoxycarbonyl)(2-hydroxyethyl)amino)methyl)nicotinate

Into a 25-mL round-bottom flask, was placed methyl5-bromo-6-[[(2-hydroxyethyl)amino]methyl]pyridine-3-carboxylate (500 mg,1.73 mmol, 1 equiv), THF (10 mL), di-tert-butyl dicarbonate (416 mg,1.91 mmol, 1.10 equiv), and Et₃N (350 mg, 3.47 mmol, 2 equiv). Theresulting mixture was stirred for 1 h at 25° C. and then concentrated.The residue was purified by silica gel chromatography (EtOAc/pet. ether,1:3) to afford the title compound as a yellow-green oil (0.55 g, 82%yield). MS: (ES, m/z): 389 [M+H]⁺.

Step-6: 4-(tert-Butyl) 8-methyl2,3-dihydropyrido[2,3-f][1,4]oxazepine-4,8(5H)-dicarboxylate

Into a 100-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed Pd(OAc)₂ (87 mg, 0.39 mmol,0.05 equiv), Johnphos (0.184 g, 0.08 equiv), Cs₂CO₃ (3.784 g, 11.61mmol, 1.5 equiv) and 1,4-dioxane (30 mL). This was followed by theaddition of a solution of methyl5-bromo-6-(((tert-butoxycarbonyl)(2-hydroxyethyl)amino)methyl)nicotinate(3 g, 7.71 mmol, 1 equiv) in 1,4-dioxane (20 mL). The resulting mixturewas stirred for 16 h at 95° C. in an oil bath. The reaction mixture wascooled to room temperature and diluted with EtOAc (50 mL) and H₂O (50mL). The resulting solution was washed with brine (3×50 mL). The organicphase was dried over anhydrous Na₂SO₄, filtered, and concentrated. Theresidue was purified by silica gel chromatography (CH₂Cl₂/MeOH, 20:1) toafford the title compound as an orange solid (1.2 g, 50% yield). MS:(ES, m/z): 309 [M+H]⁺.

Step-7: Methyl2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine-8-carboxylate

Into a 100-mL round-bottom flask, was placed 4-(tert-butyl) 8-methyl2,3-dihydropyrido[2,3-f][1,4]oxazepine-4,8(5H)-dicarboxylate (1.2 g,3.89 mmol, 1 equiv), CH₂Cl₂ (40 mL) and TFA (5 mL). The resultingsolution was stirred for 2 h at 25° C. The pH value of the solution wasadjusted to 7-8 with NaHCO₃. The solution was dried over anhydrousNa₂SO₄, filtered, and concentrated. The residue was purified by silicagel chromatography (CH₂Cl₂/MeOH, 10:1) to afford the title compound asan orange solid (0.6 g, 74% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm):8.88 (s, 1H), 7.90 (s, 1H), 4.23 (s, 2H), 4.12-4.08 (t, 2H), 3.94 (s,3H), 3.30-3.17 (t, 2H). MS: (ES, m/z): 209 [M+H]⁺.

Step-8: Methyl4-((4-methoxyphenyl)carbamoyl)-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine-8-carboxylate

Into a 10-mL round-bottom flask, was placed methyl2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine-8-carboxylate (50 mg, 0.24mmol, 1 equiv), 1-isocyanato-4-methoxybenzene (43 mg, 0.29 mmol, 1.2equiv), Et₃N (73 mg, 0.72 mmol, 3 equiv) and CH₂Cl₂ (3 mL). Theresulting mixture was stirred for 3 h at 25° C. and concentrated undervacuum. The residue was purified by silica gel chromatography(CH₂Cl₂/MeOH, 20:1) to afford the title compound as a yellow oil (60 mg,70% yield). MS: (ES, m/z): 358 [M+H]⁺.

Step-9:8-N-Hydroxy-4-N-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-4,8-dicarboxamide

Into a 25-mL round-bottom flask, was placed methyl4-((4-methoxyphenyl)carbamoyl)-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine-8-carboxylate(60 mg, 0.17 mmol, 1 equiv), aq. 1N NaOH (0.34 mL, 2 equiv), NH₂OH (50%in water, 0.33 g, 30 equiv), THF/MeOH (4:1, 2 mL). The resultingsolution was stirred for 1 h at 25° C. The pH value of the solution wasadjusted to 6 with 1N HCl. The crude product was purified by Prep-HPLC(Column HSS C18 OBD, 1.8 μm, 2.1×50 mm; Mobile Phase A: Water/0.05% TFA;Mobile Phase B: MeCN/0.05% TFA; Flow rate: 0.7 mL/min; Gradient: 5% B to23% B in 6 min, hold 1 min; Detector, UV 254, 220 nm) to afford thetitle compound as an off-white solid (31 mg, 52% yield). ¹H-NMR (400MHz, DMSO-d₆) δ(ppm): 11.35 (s, 1H), 8.45-8.51 (t, 2H), 7.61-7.62 (d,1H), 7.25-7.28 (m, 2H), 6.78-6.82 (m, 2H), 4.88-4.94 (d, 2H), 4.31-4.32(d, 2H), 3.88-3.92 (d, 2H), 3.68-3.74 (d, 3H). MS: (ES, m/z): 359[M+H]⁺.

Example 62—Preparation ofN-hydroxy-4-((4-methoxyphenyl)sulfonyl)-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine-8-carboxamide

Step-1: Methyl4-((4-methoxyphenyl)sulfonyl)-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine-8-carboxylate

Into a 10-mL round-bottom flask, was placed methyl2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine-8-carboxylate (100 mg,0.48 mmol, 1 equiv), 4-methoxybenzene-1-sulfonyl chloride (249 mg, 1.20mmol, 2.5 equiv), 4-dimethylaminopyridine (29 mg, 0.24 mmol, 0.5 equiv),Et₃N (146 mg, 1.44 mmol, 3 equiv) and CH₂Cl₂ (3 mL). The resultingmixture was stirred for 3 h at 25° C. The reaction was then quenched bythe addition of NH₄Cl. The resulting solution was extracted with CH₂Cl₂(3×10 mL). The combined organic layers were dried over anhydrous Na₂SO₄,filtered, and concentrated under vacuum. The residue was purified bysilica gel chromatography (CH₂Cl₂/MeOH, 20:1) to afford the titlecompound as a yellow solid (100 mg, 55% yield). MS: (ES, m/z): 379[M+H]⁺.

Step-2:N-Hydroxy-4-((4-methoxyphenyl)sulfonyl)-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine-8-carboxamide

Into a 25-mL round-bottom flask, was placed methyl4-((4-methoxyphenyl)sulfonyl)-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine-8-carboxylate(110 mg, 0.29 mmol, 1 equiv), aq. 1N NaOH (0.58 mL, 2 equiv), and NH₂OH(50% in water, 0.57 g, 30 equiv), THF/MeOH (4:2, 2 mL). The resultingsolution was stirred for 1 h at 25° C. The pH value of the solution wasadjusted to 6 with 1N HCl. The crude product was purified by Prep-HPLC(Column: HSS C18 OBD, 1.8 μm, 2.1×50 mm; Mobile Phase A: Water/0.05%TFA; Mobile Phase B: MeCN/0.05% TFA; Flow rate: 0.7 mL/min; Gradient: 5%B to 23% B in 6 min, hold 1 min; Detector, UV 254, 220 nm) to afford thetitle compound as an off-white solid (36 mg, 33% yield). ¹H-NMR (400MHz, DMSO-d₆) δ(ppm): 11.35 (s, 1H), 8.50 (d, 1H), 7.52-7.57 (m, 2H),7.39-7.40 (d, 1H), 6.94-6.98 (m, 2H), 4.69 (s, 2H), 4.19-4.22 (t, 2H),3.78 (s, 3H), 3.64-3.68 (t, 2H). MS: (ES, m/z): 380 [M+H]⁺.

Example 63—Preparation ofN-hydroxy-4-(4-methoxybenzyl)-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine-8-carboxamide

Step-1: Methyl4-(4-methoxybenzyl)-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine-8-carboxylate

Into a 10-mL 2-necked round-bottom flask, was placed methyl4-(4-methoxybenzyl)-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine-8-carboxylate(100 mg, 0.48 mmol, 1 equiv) and THF (4 mL) and then sodium hydride (23mg, 0.96 mmol, 1.2 equiv) was added at 0° C. The resulting mixture wasstirred for 0.5 h at 0° C. And then 1-(bromomethyl)-4-methoxybenzene (87mg, 0.43 mmol, 0.9 equiv) was added. The resulting mixture was stirredfor an additional 3 h at 25° C. The reaction was then quenched by theaddition of NH₄Cl. The resulting solution was extracted with EtOAc (3×10mL). The combined organic layers were dried over anhydrous Na₂SO₄,filtered, and concentrated under vacuum. The residue was purified bysilica gel chromatography (CH₂Cl₂/MeOH, 20:1) to afford the titlecompound as a yellow oil (100 mg, 63% yield). MS: (ES, m/z): 329 [M+H]⁺.

Step-2:N-Hydroxy-4-(4-methoxybenzyl)-2,3,4,5-tetrahydropyrido[2,3-f][1,4]oxazepine-8-carboxamide

Into a 25-mL round-bottom flask, was placed methyl4-[(4-methoxyphenyl)methyl]-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxylate(100 mg, 0.31 mmol, 1 equiv), aq. 1N NaOH (0.61 mL, 2 equiv), NH₂OH (0.6g, 30 equiv, 50% in water) and MeOH/THF (4:1, 2 mL). The resultingsolution was stirred for 1 h at 25° C. The pH value of the solution wasadjusted to 6 with 3N HCl. The crude product was purified by Prep-HPLC(Column HSS C18 OBD, 1.8 μm, 2.1×50 mm; Mobile Phase A: Water/0.05% TFA;Mobile Phase B: MeCN/0.05% TFA; Flow rate: 0.7 mL/min; Gradient: 5% B to23% B in 6 min, hold 1 min; Detector, UV 254, 220 nm) to afford thetitle compound as an orange solid (11 mg, 8% yield). ¹H-NMR (400 MHz,DMSO-d₆) δ(ppm): 11.49 (s, 1H), 9.35-10.56 (d, 1H), 8.63 (s, 1H), 7.77(s, 1H), 7.43-7.45 (d, 2H), 7.02-7.12 (t, 2H), 3.87-4.52 (m, 8H),3.76-3.79 (d, 3H). MS: (ES, m/z): 330 [M+H]⁺.

Example 64—Preparation ofN8-hydroxy-N4-(4-methoxyphenyl)-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4,8(5H)-dicarboxamide

Step-1: 2-(Methoxycarbonyl)-5-methylpyridine 1-oxide

Into a 3 L 3-necked round-bottom flask, was placed methyl5-methylpicolinate (43.7 g, 289 mmol, 1 equiv) and CH₂Cl₂ (1 L). Thiswas followed by the addition of 3-chlorobenzene-1-carboperoxoic acid(106 g, 614 mmol, 2 equiv) in several batches at 0° C. The resultingmixture was stirred overnight at room temperature. The reaction was thenquenched with sat. aq. Na₂SO₃ (500 mL) and extracted with CH₂Cl₂ (3×100mL) The combined organic layers were washed with sat. aq. NaHCO₃solution (400 mL), dried over anhydrous Na₂SO₄, filtered, andconcentrated under vacuum. The crude product was re-crystallized frompet. ether:CH₂Cl₂ (20:1) to afford the title compound as a yellow solid(40 g, 83% yield). MS: (ES, m/z): 168 [M+H]⁺.

Step-2: Methyl 6-chloro-5-methylpyridine-2-carboxylate

Into a 100-mL round-bottom flask, was placed2-(methoxycarbonyl)-5-methylpyridine 1-oxide (10 g, 59.82 mmol, 1 equiv)and chloroform (50 mL), followed by the addition of phosphoryltrichloride (42.2 mL, 9 equiv) dropwise with stirring. The resultingsolution was stirred overnight at 80° C. in an oil bath. The resultingmixture was concentrated under vacuum and then quenched with water (20mL). The pH value of the solution was adjusted to 7 with K₂CO₃ (10% inwater) and extracted with EtOAc (3×20 mL). The combined organic layerswere washed with H₂O (3×20 mL), dried over anhydrous Na₂SO₄, filtered,and concentrated under vacuum. The residue was purified by silica gelchromatography (Gradient 0-10% MeOH/CH₂Cl₂) to afford the title compoundas a yellow solid (7 g, 57% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm):7.96-8.02 (m, 2H), 3.88 (s, 1H), 2.41-2.51 (m, 3H). MS: (ES, m/z): 186[M+H]⁺.

Step-3: Methyl 5-(bromomethyl)-6-chloropyridine-2-carboxylate

Into a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed methyl6-chloro-5-methylpyridine-2-carboxylate (4.2 g, 22.63 mmol, 1 equiv),benzoyl peroxide (549.9 mg, 2.27 mmol, 0.1 equiv), NBS (4.04 g, 22.70mmol, 1 equiv) and CCl₄ (35 mL). The resulting mixture was stirredovernight at 80° C. in an oil bath. The reaction was concentrated undervacuum and quenched with water (20 mL), then extracted with EtOAc (3×30mL). The combined organic layers were washed with H₂O (3×20 mL), anddried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum.The residue was purified by silica gel chromatography (Gradient 0-10%MeOH/CH₂Cl₂) to afford the title compound as a yellow solid (2.5 g, 38%yield). MS: (ES, m/z): 265 [M+H]⁺.

Step-4: Methyl 6-chloro-5-(((2-hydroxyethyl)amino)methyl)picolinate

Into a 50-mL round-bottom flask, was placed a solution of2-aminoethan-1-ol (1.4 g, 22.89 mmol, 2 equiv) in MeCN (20 mL) and K₂CO₃(4.74 g, 34.03 mmol, 3 equiv). This was followed by the addition of asolution of methyl 5-(bromomethyl)-6-chloropyridine-2-carboxylate (3 g,11.34 mmol, 1 equiv) in MeCN (10 mL) dropwise with stirring. Theresulting mixture was stirred for 1 h at room temperature. The solidswere filtered out. The filtrate was concentrated under vacuum. Theresidue was purified by silica gel chromatography (Gradient 0-10%MeOH/CH₂Cl₂) to afford the title compound as a yellow solid (1.5 g, 49%yield). MS: (ES, m/z): 245 [M+H]⁺.

Step-5: Isopropyl2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine-8-carboxylate

Into 20-mL sealed tube, was placed methyl6-chloro-5-(((2-hydroxyethyl)amino)methyl)picolinate (1 g, 4.09 mmol, 1equiv), K₂CO₃ (1.103 g, 7.98 mmol, 2 equiv), isopropanol (10 mL) and CuI(156 mg, 0.82 mmol, 0.2 equiv). The resulting solution was stirredovernight at 110° C. in an oil bath. The reaction was then quenched withwater (10 mL) and extracted with EtOAc (3×10 mL). The combined organiclayers were washed with H₂O (3×10 mL), dried over anhydrous Na₂SO₄,filtered, and concentrated under vacuum. The residue purified by silicagel chromatography (Gradient 0-10% MeOH/CH₂Cl₂) to afford the titlecompound as a green solid (148 mg, 14% yield). MS: (ES, m/z): 237[M+H]⁺.

Step-6: Isopropyl4-((4-methoxyphenyl)carbamoyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, was placed a solution of isopropyl2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine-8-carboxylate (30 mg, 0.13mmol, 1 equiv) in CH₂Cl₂ (1.5 mL) and Et₃N (14 mg, 0.14 mmol, 1.1equiv). The resulting mixture was stirred for 30 min at 0° C. This wasfollowed by the addition of a solution of 1-isocyanato-4-methoxybenzene(21 mg, 0.14 mmol, 1.1 equiv) in CH₂Cl₂ (1 mL) dropwise with stirring at0° C. The mixture was stirred for 4 h at room temperature and thenconcentrated. The residue purified by silica gel chromatography(Gradient 0-40% EtOAc/pet. ether) to afford the title compound as ayellow oil (42 mg, 86% yield). MS: (ES, m/z): 386 [M+H]⁺.

Step-7:N8-Hydroxy-N4-(4-methoxyphenyl)-2,3-dihydropyrido[3,2-f][1,4]oxazepine-4,8(5H)-dicarboxamide

Into a 8-mL vial, was placed isopropyl4-((4-methoxyphenyl)carbamoyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine-8-carboxylate(42 mg, 0.11 mmol, 1 equiv), NH₂OH (0.864 g, 120 equiv, 50% in water),aq. 1N NaOH (0.218 mL, 2 equiv), THF/MeOH (2 mL, 4:1). The resultingmixture was stirred for 1 h at room temperature, then cooled to 0° C.and the pH value of the solution was adjusted to 6 with 6N HCl. Thecrude product was purified by Prep-HPLC (Column: HSS C18 OBD, 1.8 μm,2.1×50 mm; Mobile Phase A: Water/0.05% TFA; Mobile Phase B: MeCN/0.05%TFA; Flow rate: 0.7 mL/min; Gradient: 5% B to 95% B in 2 min, hold 0.6min; Detector, UV 254, 220 nm) to afford the title compound as a pinksolid (17 mg, 32% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.23 (s,1H), 9.01 (s, 1H), 8.42 (s, 1H), 7.92-7.94 (d, J=8 Hz, 1H), 7.64-7.66(d, J=8 Hz, 1H), 7.26-7.28 (d, J=8 Hz, 1H), 6.78-6.80 (d, J=8 Hz, 1H),4.71 (s, 1H), 4.33-4.35 (t, J=4 Hz, 2H), 3.89-3.90 (t, J=4 Hz, 2H), 3.34(s, 3H). MS: (ES, m/z): 359 [M+H]⁺.

Example 65—Preparation ofN-hydroxy-4-((4-methoxyphenyl)sulfonyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine-8-carboxamide

Step-1: Isopropyl4-((4-methoxyphenyl)sulfonyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, was placed isopropyl2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine-8-carboxylate (30 mg, 0.13mmol, 1 equiv), CH₂Cl₂ (2.5 mL) and Et₃N (14 mg, 0.14 mmol, 1.10 equiv).The resulting mixture was stirred for 30 min at 0° C. This was followedby the addition of 4-methoxybenzene-1-sulfonyl chloride (26.18 g, 112mmol, 1 equiv) dropwise with stirring at 0° C. The mixture was allowedto react, with stirring, for additional 2 h at room temperature andconcentrated. The residue purified by silica gel chromatography(Gradient 0-5% MeOH/CH₂Cl₂) to afford the title compound as a brownsolid (57 mg) which was used without further purification. MS: (ES,m/z): 407 [M+H]⁺.

Step-2:N-Hydroxy-4-((4-methoxyphenyl)sulfonyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed a solution of isopropyl4-((4-methoxyphenyl)sulfonyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine-8-carboxylate(57 mg, 0.14 mmol, 1 equiv) in THF/MeOH (2 mL, 4:1), NH₂OH (1.11 g,16.82 mmol, 120 equiv, 50% in water), and aq. 1N NaOH (0.28 mL, 2equiv). The mixture was stirred for 1 h at room temperature. The pHvalue of the solution was adjusted to 6 with 6N HCl. The crude productwas purified by Prep-HPLC (Column: HSS C18 OBD, 1.8 μm, 2.1×50 mm;Mobile Phase A: Water/0.05% TFA; Mobile Phase B: MeCN/0.05% TFA; Flowrate: 0.7 mL/min; Gradient: 5% B to 95% B in 2 min, hold 0.6 min;Detector, UV 254, 220 nm) to afford the title compound as a pink solid(13 mg, 19% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.19 (s, 1H),9.01 (s, 1H), 7.87-7.89 (d, J=8 Hz, 1H), 7.60-7.64 (m, 3H), 6.99-7.01(d, J=8 Hz, 2H), 4.54 (s, 2H), 4.26-4.28 (t, J=4 Hz, 2H), 3.76 (s, 3H),3.62-3.63 (t, J=8 Hz, 2H). MS: (ES, m/z): 380 [M+H]⁺.

Example 66—Preparation ofN-hydroxy-4-(4-methoxybenzyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine-8-carboxamide

Step-1: Isopropyl4-(4-methoxybenzyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine-8-carboxylate

Into a 8-mL vial, was placed isopropyl2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine-8-carboxylate (50 mg, 0.21mmol, 1 equiv), 4-methoxybenzaldehyde (30.25 mg, 0.22 mmol, 1.05 equiv)and CH₂Cl₂ (1.5 mL). The resulting mixture was stirred for 30 min atroom temperature. Then NaBH(OAc)₃ (449 mg, 2.12 mmol, 10 equiv) wasadded. The mixture was stirred overnight at room temperature andconcentrated. The residue purified by silica gel chromatography(Gradient 0-40% EtOAc.pet. ether) to afford the title compound as ayellow oil (59 mg, 78% yield). MS: (ES, m/z): 357 [M+H]⁺.

Step-2:N-Hydroxy-4-(4-methoxybenzyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine-8-carboxamide

Into a 8-mL vial, was placed isopropyl4-(4-methoxybenzyl)-2,3,4,5-tetrahydropyrido[3,2-f][1,4]oxazepine-8-carboxylate(63 mg, 0.18 mmol, 1 equiv), NH₂OH (1.4 g, 120 equiv, 50% in water), aq.1N NaOH (0.35 mL, 2 equiv) and THF/MeOH (2 mL, 4:1). The resultingmixture was stirred for 1 h at room temperature. The pH value of thesolution was adjusted to 6 with 6N HCl. The crude product was purifiedby Prep-HPLC (Column: HSS C18 OBD, 1.8 μm, 2.1×50 mm; Mobile Phase A:Water/0.05% TFA; Mobile Phase B: MeCN/0.05% TFA; Flow rate: 0.7 mL/min;Gradient: 5% B to 95% B in 2 min, hold 0.6 min; Detector, UV 254, 220nm) to afford the title compound as a pink solid (33 mg, 42% yield).¹H-NMR (400 MHz, DMSO-d₆) δ(ppm): 11.39 (s, 1H), 10.60 (br s, 1H), 9.11(br s, 1H), 7.94 (s, 1H), 7.76-7.78 (d, J=8 Hz, 1H), 7.42 (s, 2H),7.01-7.03 (d, J=8 Hz, 2H), 4.28-4.69 (m, 7H), 3.71-3.86 (m, 4H). MS:(ES, m/z): 330 [M+H]⁺.

Example 67—Preparation ofN-Hydroxy-4-(4-methoxybenzyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Dimethyl 2-hydroxyterephthalate

2-Hydroxyterephthalic acid (5 g, 27.5 mmol) was refluxed in MeOH (120mL), containing 0.15 mL of conc. H₂SO₄. After 22 h the reaction mixturewas concentrated under reduced pressure and the residue was redissolvedin CH₂Cl₂ and washed sequentially with water, saturated aqueous solutionof NaHCO₃, brine and dried over Na₂SO₄. The solution was filtered andconcentrated. The crude material was purified by silica gelchromatography (Gradient: EtOAc/hexanes) to afford the title compound(1.7 g, 31% yield).

Step-2: Dimethyl 2-(2-((tert-butoxycarbonyl)amino)ethoxy)terephthalate

To a suspension of dimethyl 2-hydroxyterephthalate (0.7 g, 3.3 mmol, 1equiv) in THF (8 mL), tert-butyl (2-hydroxyethyl)carbamate (0.62 mL, 4.0mmol, 1.2 equiv) and triphenylphosphine (1.4 g, 5.3 mmol, 1.6 equiv)were added at room temperature. The mixture was cooled to 0° C. and DEAD(0.84 mL, 5.3 mmol, 1.6 equiv) was added and the resulting mixture wasslowly warmed up to room temperature and stirred 72 h. The mixture wasconcentrated and purified by silica gel chromatography (Gradient:EtOAc/hexanes) to afford the title compound (1.15 g, quantitativeyield).

Step-3: Dimethyl 2-(2-aminoethoxy)terephthalate

Dimethyl 2-(2-((tert-butoxycarbonyl)amino)ethoxy)terephthalate (1.18 g,3.34 mmol) was mixed with CH₂Cl₂ (3 mL) and then TFA (1.5 mL) was addedat room temperature. The reaction mixture was stirred overnight at roomtemperature, then concentrated and co-evaporated several times withtoluene. After trituration in MeOH/Et₂O the title compound was obtainedas its TFA salt (1.15 g, quantitative yield).

Step-4: Methyl5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Dimethyl 2-(2-aminoethoxy)terephthalate (1.15 g, 3.3 mmol) was mixedwith toluene (7 mL) and Et₃N (1.9 mL, 13.3 mmol) and stirred at 105° C.After 20 h, the reaction mixture was cooled to room temperature,concentrated and purified by silica gel chromatography (GradientEtOAc/hexanes) to afford the title compound (380 mg, 52% yield). m.p.=149-150° C. ¹H-NMR (300 MHz, CDCl₃) δ(ppm): 8.0.2 (d, J=8.25 Hz, 1H),7.87, (d, J=8.25 Hz, 1H), 7.76 (dd, J=8.25, 1.65 Hz, 1H), 7.25 (d,J=8.25 Hz, 1H), 6.73 (br. s, 1H), 4.44-4 (m, 2H), 3.93 (s, 3H),3.54-3.50 (m, 2H). MS: (APCI, m/z): 222 [M+H]⁺.

Step-5: Methyl4-(4-methoxybenzyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Sodium hydride (60% dispersion in mineral oil, 8.14 mg, 0.203 mmol, 1.5equiv) was added to a solution of methyl5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (30 mg,0.136 mmol, 1 equiv) in DMF (1.4 mL) and the solution was stirred atroom temperature for 30 minutes. 1-(Bromomethyl)-4-methoxybenzene (57μL, 0.407 mmol, 3 equiv) was added and the reaction was stirred at 50°C. overnight. The reaction mixture was partitioned between EtOAc andsaturated aqueous solution of NaHCO₃. The layers were separated and theorganic layer was washed with brine, dried over Na₂SO₄, filtered andconcentrated. The residue was purified by silica gel chromatography(Gradient 20-80% EtOAc/hexanes) to afford the title compound as acolorless oil.

Step-6:N-Hydroxy-4-(4-methoxybenzyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

To a solution of methyl4-(4-methoxybenzyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(46 mg, 0.136 mmol, 1 equiv) in MeOH (272 μL) and THF (1 mL) was addedan aqueous 50% wt hydroxylamine solution (167 μL, 2.72 mmol, 20 equiv)and aqueous 2N NaOH solution (136 μL, 0.272 mmol, 2 equiv). The reactionwas stirred at room temperature for 2 h. The reaction was acidified with2N HCl and extracted with EtOAC. The organic layer was washed with waterand brine, dried over Na₂SO₄, filtered and concentrated. The residue waspurified by Prep-HPLC (Column: XBridge RP C18 OBD, 5 M, 19×50 mm; MobilePhase A: Water/0.1% Formic Acid; Mobile Phase B: MeCN/0.1% Formic Acid;Flow rate: 23 mL/min; Gradient: 10% B to 70% B in 7 min) to afford thetitle compound (22 mg, 47% over 2 steps). ¹H-NMR (300 MHz, DMSO-d₆)δ(ppm): 11.28 (br s, 1H), 9.15 (br s, 1H), 7.73 (d, J=7.9 Hz, 1H), 7.51(dd, J=8.1, 1.6 Hz, 1H), 7.15-7.40 (m, 3H), 6.73-7.06 (m, 2H), 4.65 (s,2H), 4.18 (t, J=5.0 Hz, 2H), 3.68-3.76 (m, 3H), 3.46 (t, J=5.1 Hz, 2H).MS: (ES, m/z): 343 [M+H]⁺.

TABLE 31 The following compound was prepared according to the method ofExample 67. Found Structure M + H ¹H-NMR (300 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 357 [M + H]⁺ 11.30 (s, 1 H), 9.13 (s, 1 H), 7.66 (d, J = 7.9Hz, 1 H), 7.48 (dd, J = 8.1, 1.6 Hz, 1 H), 7.32 (d, J = 1.5 Hz, 1 H),7.16 (m, J = 8.8 Hz, 2 H), 6.79-6.89 (m, 2 H), 4.24 (t, J = 5.0 Hz, 2H), 3.64-3.72 (m, 5 H), 3.46 (br t, J = 5.0 Hz, 2 H), 2.73-2.84 (m, 2 H)

Example 68—Preparation ofN-Hydroxy-4-(4-methoxybenzyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carboxamide

Step-1: Dimethyl 4-hydroxyisophthalate

Under a nitrogen purge, 4-hydroxyisophthalic acid (10.9 g, 0.06 mol) wasdissolved in MeOH (85 mL) in a 250 mL 3-neck round-bottomed flask.Sulfuric acid (98%, 8.5 mL) was placed in an addition funnel and addeddropwise over 25 min, resulting in an exotherm to 35° C. After theaddition was completed, the reaction was heated to a gentle reflux, andmaintained for 28 h. Upon removal of heat source, a white precipitatebegan to form. The flask was further cooled in an ice bath, and thesolids were then isolated by filtration. The solid was washed with coldisopropanol and then with hexanes, and then allowed to dry on thefilter, providing the title compound as a white solid (10.4 g, 82%yield).

Step-2: Dimethyl 4-(2-((tert-butoxycarbonyl)amino)ethoxy)isophthalate

Under a nitrogen purge, dimethyl 4-hydroxyisophthalate (2.10 g 0.01 mol)was dissolved in MeCN (70 mL) in a 250 mL 3-neck round-bottomed flask.18-Crown-6 (0.13 g, 5 mol %) and potassium carbonate (1.5 g, 0.011 mol)were added sequentially, in single portions, washing in with MeCN (10mL). Tert-butyl(2-bromoethyl)carbamate (2.24 g, 0.01 mol) was added in asingle portion, and washed in with MeCN (5 mL). The resulting suspensionwas heated at reflux for 16 h. Heat was removed, and the reactionmixture was cooled in an ice/acetone bath. Solids were removed byfiltration, and the filter cake was washed with more MeCN. The filtratewas pre-absorbed directly onto silica gel, and purified by silica gelchromatography (Gradient 15-50% EtOAc/hexanes) to afford the titlecompound as an amber oil which slowly solidified (1.1 g, 31% yield).

Step-3: Methyl5-oxo-2,3,4,5-tetrahydrobenzon[f][1,4]oxazepine-7-carboxylate

Dimethyl 4-(2-((tert-butoxycarbonyl)amino)ethoxy)isophthalate (2.2 g,6.2 mmol) was dissolved in CH₂Cl₂ (12 mL) in a 50 mL round-bottomedflask. TFA (4 mL) was added in a single portion, and the resultingsolution was stirred for 16 h. Solvent was removed under reducedpressure to provide an oil. Five times, toluene was added and removedunder reduced pressure. The resulting solid was suspended in toluene (40mL), and Et₃N (3.5 mL, 0.025 mol) was added in a single portion. Uponheating to reflux, all solids slowly dissolved to provide a clearsolution. The reaction was heated for another 16 h, then partitionedbetween EtOAc and water. The organic layer was washed with water andbrine, dried over MgSO₄, filtered and concentrated. Purification byrecrystallization from 2-propanol afforded the title compound as a palebeige solid (0.65 g, 47% yield). ¹H-NMR (300 MHz, CDCl₃) δ(ppm):3.54-3.61 (m, 2H) 3.90 (s, 3H) 4.45-4.51 (m, 2H) 7.04 (d, J=8.53 Hz, 1H)7.42 (br. s., 1H) 8.07 (dd, J=8.53, 2.20 Hz, 1H) 8.76 (d, J=2.20 Hz,1H).

Step-4: Methyl4-(4-methoxybenzyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carboxylate

Sodium hydride (60% dispersion in mineral oil, 13 mg, 0.325 mmol, 1.5equiv) was added to a solution of methyl5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carboxylate (48 mg,0.217 mmol, 1 equiv) in DMF (2.2 mL) and the solution was stirred atroom temperature for 30 minutes. 1-(Bromomethyl)-4-methoxybenzene (33.5μL, 0.239 mmol, 1.1 equiv) was added and the reaction was stirred at 50°C. overnight. The reaction mixture was partitioned between EtOAc andsaturated aqueous solution of NaHCO₃. The layers were separated and theorganic layer was washed with brine, dried over Na₂SO₄, filtered andconcentrated. The residue was purified by silica gel chromatography(Gradient 20-80% EtOAc/hexanes) to afford the title compound as a whitesolid (33 mg, 45% yield). MS: (ES, m/z): 342 [M+H]⁺.

Step-5:N-Hydroxy-4-(4-methoxybenzyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carboxamide

To a solution of methyl4-(4-methoxybenzyl)-5-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-7-carboxylate(33 mg, 0.097 mmol, 1 equiv) in MeOH (152 μL) and THF (608 μL) was addedNH₂OH (50% in water, 118 μL, 1.94 mmol, 20 equiv) and aq. 2N NaOH (97μL, 0.194 mmol, 2 equiv). The reaction was stirred at room temperaturefor 3 days. The reaction was directly purified by Prep-HPLC (Column:XBridge RP C18 OBD, 5 μM, 19×50 mm; Mobile Phase A: Water/0.1% FormicAcid; Mobile Phase B: MeCN/0.1% Formic Acid; Flow rate: 23 mL/min;Gradient: 10% B to 70% B in 7 min) to afford the title compound as anoil (3.5 mg, 13% yield). ¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 10.3 (s, 1H),8.33 (s, 1H), 8.15 (s, 1H), 7.83-7.76 (m, 1H), 7.25 (br d, J=7.3 Hz,2H), 7.03 (br d, J=8.5 Hz, 1H), 6.89 (br d, J=8.5 Hz, 2H), 4.65 (s, 2H),4.22 (br s, 2H), 3.71 (s, 3H), 3.48 (br s, 2H). MS: (ES, m/z): 343[M+H]⁺.

TABLE 32 The following compound was prepared according to the method ofExample 68. Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 357 [M + H]⁺

Example 69—Preparation ofN-hydroxy-4-(4-methoxyphenethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-8-carboxamide

Step-1: Methyl 4-(((2-methoxy-2-oxoethyl)amino)methyl)-3-nitrobenzoate

To a solution of methyl 4-(bromomethyl)-3-nitrobenzoate (5.2 g, crude,18.3 mmol) and methyl 2-aminoacetate hydrochloride (6.86 g, 54.9 mmol)in DMF (15 mL,) stirred at room temperature, was added DIEA (12.7 mL,73.2 mmol) dropwise. After 5 hours, it was diluted with Et₂O (120 mL),washed with water (3×80 mL) and brine (80 mL), dried over Na₂SO₄,filtered and concentrated under reduced pressure. The brown solidresidue was purified by silica gel chromatography (Gradient 0-100%EtOAc/hexanes) to give the title compound (4.2 g)

Step-2: Methyl4-(((tert-butoxycarbonyl)(2-methoxy-2-oxoethyl)amino)methyl)-3-nitrobenzoate

To a solution of methyl4-(((2-methoxy-2-oxoethyl)amino)methyl)-3-nitrobenzoate (4.2 g, 15 mmol)in EtOAc/hexanes (200 mL, 1:1) stirred at room temperature, was addeddi-tert-butyl dicarbonate (3.4 g, 15.6 mmol) followed by4-dimethylaminopyridine (50 mg). The reaction was stirred at roomtemperature overnight. TLC indicated there was still a lot of startingmaterial. More di-tert-butyl dicarbonate (2.0 g, 9.2 mmol) was added andthe mixture was stirred for another 3 hours. It was concentrated underreduced pressure. The residue was purified by silica gel chromatography(Gradient 0-100% EtOAc/hexanes) to give the title compound as a yellowoil (4.9 g, 70% yield over 3 steps).

Step-3: Methyl3-amino-4-(((tert-butoxycarbonyl)(2-methoxy-2-oxoethyl)amino)methyl)benzoate

To a solution of methyl4-(((tert-butoxycarbonyl)(2-methoxy-2-oxoethyl)amino)methyl)-3-nitrobenzoate(4.9 g, 12.8 mmol) in MeOH (100 mL) was added 10% Pd/C (2.5 g). Themixture was purged with N₂ for 10 min and then stirred under a hydrogenballoon for 16 h. The mixture was filtered through Celite and thefiltrate was evaporated under reduced pressure to give the titlecompound as a greenish gum (4.0 g, 89% yield).

Step-4: 4-(tert-Butyl) 8-methyl2-oxo-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4,8-dicarboxylate

A solution of methyl3-amino-4-(((tert-butoxycarbonyl)(2-methoxy-2-oxoethyl)amino)methyl)-benzoate(4.0 g, 13 mmol) in anhydrous toluene (100 mL) was stirred under refluxovernight. After removal of solvent under reduced pressure, the residuewas purified by silica gel chromatography (Gradient 10-100%EtOAc/hexanes) to give the title compound as an off-white solid (0.96 g,27% yield).

Step-5: Methyl2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-8-carboxylate

To a solution of HCl in dioxane (4M, 30 mL) was added 4-(tert-butyl)8-methyl2-oxo-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4,8-dicarboxylate(956 mg, 2.98 mmol). The mixture was stirred at room temperature for 5hours. The solid precipitates were collected by filtration and dried at50° C. under vacuum overnight to give the title compound as its HCl saltas an off-white solid (745 mg, 97% yield). ¹H-NMR (300 MHz, DMSO-d₆)δ(ppm): 10 69 (s, 1H), 10.17 (s, 1H), 7.79 (dd, J=7.7, 1.5 Hz, 1H), 7.70(d, J=1.6 Hz, 1H), 7.60 (d, J=7.7 Hz, 1H), 4.28 (s, 2H), 3.88 (s, 3H),3.65 (s, 2H). MS: (APCI, m/z): 221 [M-Cl]⁺.

Step-6: Methyl4-(4-methoxyphenethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-8-carboxylate

To a suspension of methyl2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-8-carboxylatehydrochloride (40 mg, 0.16 mmol, 1 equiv) and K₂CO₃ (43 mg, 0.31 mmol, 2equiv) in MeOH was added 1-(2-bromoethyl)-4-methoxybenzene (76 μL, 0.49mmol, 3 equiv). The resulting mixture was heated at 55° C. for 2 days.The reaction mixture was partitioned between EtOAc and a saturatedaqueous solution of NaHCO₃. The layers were separated. The organic layerwas washed with water, then with brine, and dried over anhydrous Na₂SO₄.The solution was filtered, and concentrated. This crude material waspurified by silica gel chromatography (Gradient 0-10% MeOH/CH₂Cl₂ with0.1% formic acid) to afford the title compound as a colorless oil (14.4mg, 26% yield). MS: (ES, m/z): 355 [M+H]⁺.

Step-7:N-Hydroxy-4-(4-methoxyphenethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-8-carboxamide

To a solution of methyl4-(4-methoxyphenethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-8-carboxylate(14 mg, 0.041 mmol, 1 equiv) in a MeOH/THF (1 mL, 1/4) was added anNH₂OH (50% in water, 212 μL, 3.5 mmol, 85 equiv) and aq. 2N NaOHsolution (40.6 μL, 0.081 mmol, 2 equiv). The reaction was stirred atroom temperature for 2 h, then was acidified with 2N HCl. The mixturewas extracted with EtOAc and the separated organic layer was washed withbrine, then dried over anhydrous Na₂SO₄. The solution was filtered, andconcentrated. This crude material was purified by Prep-HPLC (Column:XBridge RP C18 OBD, 5 M, 19×50 mm; Mobile Phase A: Water/0.1% FormicAcid; Mobile Phase B: MeCN/0.1% Formic Acid; Flow rate: 23 mL/min;Gradient: 2% B to 50% B in 7 min) to afford the title compound (7.1 mg,49% yield). ¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 11.19 (br s, 1H), 10.06(s, 1H), 8.17 (s, 1H), 7.42 (s, 1H). 7.29-7.40 (m, 2H), 7.09 (d, J=8.5Hz, 2H), 6.80 (d, J=8.5 Hz, 2H), 3.77-3.97 (m, 2H), 3.68 (s, 3H),3.27-3.33 (m, 2H), 2.65 (s, 4H). MS: (ES, m/z): 356 [M+H]⁺.

TABLE 33 The following compound was prepared according to the method ofExample 69. Structure Found M + H

(ES, m/z): 356 [M + H]⁺

Example 70—Preparation of4-((1H-benzo[d]imidazol-2-yl)methyl)-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide

Step-1: Methyl 3-(((2-methoxy-2-oxoethyl)amino)methyl)-4-nitrobenzoate

Into a 250-mL round-bottom flask that has been purged and maintainedwith an inert atmosphere of nitrogen, were placed methyl 2-aminoacetate(12 g, 135 mmol, 1.5 equiv), methyl 3-(bromomethyl)-4-nitrobenzoate (12g, 26 mmol, 1 equiv), DIEA (32 mL, 3 equiv) and DMF (120 mL). Theresulting solution was stirred for 12 h at room temperature. Thereaction was then quenched by the addition of water. The resultingsolution was extracted with EtOAc (3×100 mL) and the combined organiclayer was washed with brine (100 mL). The organic mixture was dried overanhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residuewas purified by silica gel chromatography (Gradient 1:10 to 1:1EtOAc/hexanes) to afford the title compound as a yellow solid (4.9 g,66% yield). MS: (ES, m/z): 283 [M+H]⁺.

Step-2: Methyl3-(((tert-butoxycarbonyl)(2-methoxy-2-oxoethyl)amino)methyl)-4-nitrobenzoate

Into a 100-mL round-bottom flask, were placed methyl3-(((2-methoxy-2-oxoethyl)amino)methyl)-4-nitrobenzoate (4.7 g, 16.8mmol, 1 equiv), CH₂Cl₂ (100 mL), di-tert-butyl dicarbonate (4.4 g, 20.2mmol, 1.2 equiv) and 4-dimethylaminopyridine (82 mg, 0.67 mmol, 0.04equiv). The resulting solution was stirred for 4 h at room temperature.The resulting mixture was concentrated under vacuum. The residue waspurified by silica gel chromatography (Gradient 1:10 to 1:1EtOAc/petroleum ether) to afford the title compound as a yellow oil (2.8g, 44% yield). MS: (ES, m/z): 283 [M-Boc+H]⁺.

Step-3: Methyl4-amino-3-(((tert-butoxycarbonyl)(2-methoxy-2-oxoethyl)amino)methyl)benzoate

Into a 100-mL round-bottom flask, were placed methyl3-(((tert-butoxycarbonyl)(2-methoxy-2-oxoethyl)amino)methyl)-4-nitrobenzoate(2.8 g, 7.3 mmol, 1 equiv), MeOH (30 mL) and palladium on carbon (280mg). The resulting solution was stirred for 18 h at room temperatureunder a H₂ balloon. The solids were filtered out and the filtrate wasconcentrated under reduced pressure to afford the title compound as abrown oil (1.9 g, 74% yield). MS: (ES, m/z): 253 [M-Boc+H]⁺.

Step-4: 4-(tert-Butyl) 7-methyl2-oxo-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4,7-dicarboxylate

Into a 250-mL round-bottom flask that has been purged and maintainedwith an inert atmosphere of nitrogen, were placed methyl4-amino-3-(((tert-butoxycarbonyl)(2-methoxy-2-oxoethyl)amino)methyl)benzoate(1.9 g, 7.5 mmol, 1 equiv), THF (100 mL) and sodium hydride (239 mg, 10mmol, 1.3 equiv). The resulting solution was stirred for 4 h at roomtemperature. The reaction mixture was poured into water/ice andextracted with EtOAc (3×150 mL). The combined organic layers was washedwith brine (100 mL), dried over anhydrous Na₂SO₄, filtered, andconcentrated under vacuum. The crude product was recrystallized fromdiethyl ether to afford the title compound as a white solid (0.5 g, 21%yield). ¹H-NMR (400 MHz, CDCl₃) δ(ppm): 10.34-10.41 (m, 1H), 7.76-7.79(m, 2H), 7.17-7.20 (m, 1H), 4.27-4.53 (m, 4H), 3.82 (s, 3H), 1.34 (s,3H), 1.20 (s, 6H).

Step-5: Methyl2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxylate

Into a 500-mL round-bottom flask that has been purged and maintainedwith an inert atmosphere of nitrogen, were placed 4-(tert-butyl)7-methyl2-oxo-1,2,3,5-tetrahydro-4H-benzo[e][1,4]diazepine-4,7-dicarboxylate (12g, 37 mmol, 1 equiv) and 4N HCl in dioxane (360 mL). The resultingsolution was stirred for 6 h at room temperature. The resulting mixturewas concentrated under vacuum and washed with diethyl ether (300 mL) toafford the title compound as the HCl salt as a white solid (9.5 g, 99%yield). MS: (ES, m/z): 221 [M+H]⁺.

Step-6: Methyl4-((1H-benzo[d]imidazol-2-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxylate

To a suspension of methyl2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxylatehydrochloride (50 mg, 0.195 mmol, 1 equiv) and K₂CO₃ (56.5 mg, 0.41mmol, 2.1 equiv) in MeCN (1 mL) was added2-(chloromethyl)-1H-benzo[d]imidazole (68 mg, 0.41 mmol, 2.1 equiv). Theresulting mixture was heated at 55° C. for 2 days. The reaction mixturewas partitioned between EtOAc and a saturated aqueous solution ofNaHCO₃. The layers were separated. The organic layer was washed withwater, then with brine, and dried over Na₂SO₄. The solution wasfiltered, and concentrated. This crude material was purified by silicagel chromatography (Gradient 0-5% MeOH/CH₂Cl₂) to afford the titlecompound as a yellow oil (54.5 mg, 80% yield). MS: (ES, m/z): 351[M+H]⁺.

Step-7:4-((1H-Benzo[d]imidazol-2-yl)methyl)-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide

To a solution of methyl4-((1H-benzo[d]imidazol-2-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxylate(54 mg, 0.154 mmol, 1 equiv) in a MeOH/THF (4:1, 2 mL) were added NH₂OH(50% in water, 996 μL, 16 mmol, 85 equiv) and aq. 2N NaOH solution (15μL, 0.31 mmol, 2 equiv). The reaction was stirred at room temperaturefor 2 h, then was acidified with 2N HCl. The mixture was extracted withEtOAc and the separated organic layer was washed with brine, then driedover anhydrous MgSO₄. The solution was filtered, and concentrated. Thiscrude material was purified by Prep-HPLC (Column: XBridge RP C18 OBD, 5M, 19×50 mm; Mobile Phase A: Water/0.1% Formic Acid; Mobile Phase B:MeCN/0.1% Formic Acid; Flow rate: 23 mL/min; Gradient: 2% B to 50% B in7 min) to afford the title compound (10.7 mg, 19% yield). ¹H-NMR (300MHz, DMSO-d₆) δ(ppm): 12.40 (br s, 1H), 11.12 (br s, 1H), 10.24 (s, 1H),8.15 (s, 1H), 7.59-7.67 (m, 2H), 7.38-7.56 (m, 2H), 7.07-7.16 (m, 3H),3.90 (s, 2H), 3.87 (s, 2H), 3.39 (s, 2H). MS: (ES, m/z): 352 [M+H]⁺.

TABLE 34 The following compound was prepared according to the method ofExample 70. Structure Found M + H

(ES, m/z): 356 [M + H]⁺

Example 71—Preparation ofN-hydroxy-2-oxo-4-(1-phenylethyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide

Step-1: Methyl2-oxo-4-(1-phenylethyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxylate

Into a 100-mL round-bottom flask, was placed methyl2-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxylatehydrochloride (100 mg, 0.39 mmol, 1 equiv), a solution of(1-bromoethyl)benzene (79 mg, 0.43 mmol, 1.1 equiv) in MeCN (5 mL) andDIEA (252 mg, 1.95 mmol, 5 equiv). The resulting solution was stirredovernight at 50° C. in an oil bath. The resulting mixture wasconcentrated under vacuum, diluted with H₂O (30 mL), and extracted withEtOAc (3×100 mL). The combined organic layers were concentrated andpurified by silica gel chromatography (EtOAc/pet. ether, 1:1) to affordthe title compound as a yellow solid (110 mg, 87% yield).

Step-2:N-Hydroxy-2-oxo-4-(1-phenylethyl)-2,3,4,5-tetrahydro-H-benzo[e][1,4]diazepine-7-carboxamide

Into a 100-mL round-bottom flask, was placed a solution of methyl2-oxo-4-(1-phenylethyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxylate(110 mg, 0.34 mmol, 1 equiv) in THF/MeOH (2.5 mL, 4:1), NH₂OH (50% inwater, 1 mL, 60 equiv), aq. 1N NaOH (0.5 mL, 2 equiv). The resultingsolution was stirred for 6 h at room temperature. The crude product waspurified by Prep-HPLC (Column: Xbridge RP C18 OBD, 5 μm, 19×50 mm;Mobile Phase A: Water/0.05% TFA; Mobile Phase B: MeCN/0.05% TFA; Flowrate: 30 mL/min; Gradient: 10% B to 53% B in 8 min; Detector, UV 254,220 nm) to afford the title compound as a light yellow solid (19 mg, 16%yield). ¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 11.22 (s, 1H), 10.60 (s, 1H),7.77-7.75 (d, J=6.9 Hz, 2H), 7.45-7.41 (m, 5H), 7.16-7.13 (d, J=8.4 Hz,1H), 4.16 (s, 3H) 3.52-3.44 (m, 2H), 1.55 (s, 3H). MS: (ES, m/z): 326[M+H]⁺.

Example 72—Preparation ofN-Hydroxy-4-(4-methoxybenzyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide

Step-1: Methyl4-(4-methoxybenzyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxylate

To a suspension of methyl2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxylatehydrochloride (45 mg, 0.175 mmol, 1 equiv) in 1,2-dichloroethane (1.8mL) were added p-anisaldehyde (32 μL, 0.263 mmol, 1.5 equiv) and Et₃N(24 μL, 0.175 mmol, 1 equiv). The reaction mixture was stirred at roomtemperature for 1 h. Sodium triacetoxyborohydride (93 mg, 0.438 mmol,2.5 equiv) was added to the reaction mixture and stirred at roomtemperature overnight. LCMS showed reaction completed. The reactionmixture was partitioned between CH₂Cl₂ and a saturated aqueous solutionof NaHCO₃. The layers were separated. The organic layer was washed withbrine, and dried over anhydrous Na₂SO₄. The solution was filtered, andconcentrated. This crude material was purified by silica gelchromatography (Gradient 10-100% EtOAc/hexanes) to afford the titlecompound as a white solid (47.8 mg, 80% yield). MS: (ES, m/z): 341[M+H]⁺.

Step-2:N-Hydroxy-4-(4-methoxybenzyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide

To a solution of methyl4-(4-methoxybenzyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxylate(47 mg, 0.138 mmol, 1 equiv) in a MeOH/THF (1.4 mL, 1/4) were added anaqueous 50% wt hydroxylamine solution (169 μL, 2.76 mmol, 20 equiv) andaqueous 2N NaOH solution (138 μL, 0.276 mmol, 2 equiv). The reaction wasstirred at room temperature for 2 days, then was acidified with 2N HCl.The mixture was concentrated and the residue was purified by Prep-HPLC(Column: Xbridge RP C18 OBD, 5 μm, 19×50 mm; Mobile Phase A: Water/0.1%Formic Acid; Mobile Phase B: MeCN/0.1% Formic Acid; Flow rate: 23mL/min; Gradient: 5% B to 50% B in 7 min) to afford the title compoundas a yellow oil (23 mg, 49% yield). ¹H-NMR (300 MHz, DMSO-d₆) δ(ppm):11.10 (br s, 1H), 10.18 (s, 1H), 8.11 (s, 1H), 7.57-7.66 (m, 1H), 7.53(s, 1H), 7.14-7.21 (m, 2H), 7.06 (d, J=8.5 Hz, 1H), 6.86 (br d, J=8.5Hz, 2H), 3.65-3.75 (m, 5H), 3.56 (s, 2H), 3.22 (s, 2H). MS: (ES, m/z):342 [M+H]⁺.

Example 73—Preparation ofN-Hydroxy-4-((4-methoxyphenyl)sulfonyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide

Step-1: Methyl4-((4-methoxyphenyl)sulfonyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxylate

To a suspension of methyl2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxylatehydrochloride (35 mg, 0.136 mmol, 1 equiv) in THE (1.4 mL) were addedDIEA (83 benzo, 0.477 mmol, 3.5 equiv) and 4-methoxybenzene-1-sulfonylchloride (34 mg, 0.164 mmol, 1.2 equiv). The reaction mixture wasstirred at room temperature overnight. The reaction mixture waspartitioned between EtOAc and a saturated aqueous solution of NaHCO₃.The layers were separated. The organic layer was washed with brine, anddried over anhydrous Na₂SO₄. The solution was filtered, and concentratedto afford the title compound as a white solid (52.7 mg) which was usedwithout further purification. MS: (ES, m/z): 391 [M+H]⁺.

Step-2:N-Hydroxy-4-((4-methoxyphenyl)sulfonyl)-2-oxo-2,3,4,5-tetrahydro-11-benzo[e][1,4]diazepine-7-carboxamide

To a solution of methyl4-((4-methoxyphenyl)sulfonyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxylate(49.4 mg, 0.127 mmol, 1 equiv) in a MeOH/THF (1.3 mL, 1:4) were addedNH₂OH (50% in water, 155 μL, 2.53 mmol, 20 equiv) and aq. 2N NaOHsolution (127 μL, 0.253 mmol, 2 equiv). The reaction was stirred at roomtemperature for 2 days. The reaction was acidified to pH 6 with 2N HCland the solution was directly purified by Prep-HPLC (Column: Xbridge RPC18 OBD, 5 μm, 19×50 mm; Mobile Phase A: Water/0.1% Formic Acid; MobilePhase B: MeCN/0.1% Formic Acid; Flow rate: 20 mL/min; Gradient: 5% B to70% B in 7 min) to afford the title compound as a white solid (6.3 mg,13% yield). ¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 11.12 (br s, 1H), 10.17(s, 1H), 9.01 (br s, 1H), 7.48-7.64 (m, 4H), 6.79-7 (m, 3H), 4.45 (s,2H), 4.06 (s, 2H), 3.77 (s, 3H). MS: (ES, m/z): 392 [M+H]⁺.

Example 74—Preparation ofN-Hydroxy-2-oxo-4-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide

Step-1: Methyl2-oxo-4-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxylate

A mixture of methyl2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxylate (60 mg,0.234 mmol, 1 equiv), bromobenzene (0.025 mL, 0.234 mmol, 1 equiv),sodium tert-butoxide (29.2 mg, 0.304 mmol, 1.3 equiv) and XPhos-Pd-G3(10 mg, 0.012 mmol, 0.05 equiv) in 1,4-dioxane (2 mL) was heated at 80°C. overnight. The reaction was partitioned between water and CH₂Cl₂. Theseparated aqueous layer was extracted with CH₂Cl₂, and the combinedorganic layers were concentrated to afford the title compound as a paleyellow solid (11.9 mg, 17% yield). MS: (ES, m/z): 297 [M+H]⁺.

Step-2:N-Hydroxy-2-oxo-4-phenyl-2,3,4,5-tetrahydro-H-benzo[e][1,4]diazepine-7-carboxamide

To a solution of methyl2-oxo-4-phenyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxylate(11.9 mg, 0.040 mmol) in MeOH (125 μL) and THF (500 μL) was added NH₂OH(50% in water, 209 μL, 3.41 mmol, 85 equiv) and aq. 2N NaOH solution (40μL, 0.080 mmol, 2 equiv). The reaction was stirred at room temperaturefor 1 h and was directly purified by Prep-HPLC (Column: Xbridge Prep C18OBD, 5 μm, 19×50 mm; Mobile Phase A: Water/0.1% Formic Acid; MobilePhase B: MeCN/0.1% Formic Acid; Flow rate: 20 mL/min; Gradient: 5% B to85% B in 7 min) to afford the title compound (3.3 mg, 28% yield). ¹H-NMR(300 MHz, DMSO-d₆) δ(ppm): 10.02 (s, 1H), 8.25 (s, 1H), 7.72-7.78 (m,1H), 7.04-7.23 (m, 2H), 6.91-7.04 (m, 1H), 6.79 (m, 2H), 6.56-6.71 (m,2H), 4.77 (s, 2H), 4.42 (s, 2H). MS: (ES, m/z): 298 [M+H]⁺.

Example 75—Preparation ofN-hydroxy-2-oxo-4-(piperidine-1-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide

A 2-mL reaction vial was charged with ethyl2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxylate (11 mg,0.05 mmol), bis(2,5-dioxopyrrolidin-1-yl) carbonate (14 mg, 0.055 mmol),MeCN (500 μL) and Et₃N (41.8 μL, 0.3 mmol). The vial was sealed andshaken at room temperature for 1 h. The solvent was removed under astream of nitrogen. DMA (500 μL) and piperidine (neat, 29.6 μL, 0.3mmol) were added and the vial was shaken at room temperature overnight.The mixture was diluted with brine (500 μL) and extracted with EtOAc(2×600 μL). The combined organic layers was dried under a stream ofnitrogen. A solvent mixture of THF/MeOH (3:1, 180 μL) was added to thevial and it was shaken at 50° C. for 15 min to dissolve the residue.NH₂OH (50% in water, 125 μL) was added followed by aq. 1N NaOH (85 μL)and the vial was sealed and shaken at room temperature overnight. Thesolvent was evaporated under reduce pressure. The residue was dissolvedin DMSO (500 μL), then purified by HPLC to afford the title compound(1.3 mg, 7.8% yield). MS: (ES, m/z): 333 [M+H]⁺.

Example 76—Preparation ofN-hydroxy-4-(4-methoxybenzyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide

Step-1: Methyl4-(4-methoxybenzyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxylate

To a cooled solution of methyl4-(4-methoxybenzyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxylate(56.5 mg, 0.166 mmol, 1 equiv) in DMF (1.3 mL) was added sodium hydride(10.6 mg, 0.266 mmol, 1.6 equiv). After stirring for 15 minutes incooling bath, the bath was removed and the reaction was stirred at roomtemperature for 15 minutes. Iodomethane (11.4 μL, 0.183 mmol, 1.1 equiv)was added and the reaction was stirred at room temperature overnight. Tothe reaction mixture was added a saturated aqueous solution of NaHCO₃and water. The resulting solution was extracted with CH₂Cl₂ and theorganic layer was washed with brine, dried over anhydrous Na₂SO₄,filtered, and concentrated to afford the title compound (58 mg) whichwas used without further purification. MS: (ES, m/z): 355 [M+H]⁺.

Step-2:N-Hydroxy-4-(4-methoxybenzyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide

To a solution of methyl4-(4-methoxybenzyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxylate(58 mg, 0.16 mmol, 1 equiv) in MeOH (300 μL) and THF (1.2 mL) was addedNH₂OH (50% in water, 852 μL, 13.9 mmol, 85 equiv) and aq. 2N NaOHsolution (164 μL, 0.327 mmol, 2 equiv). The reaction was stirred at roomtemperature for 2 h and was directly purified by Prep-HPLC (Column:Xbridge RP C18 OBD, 5 μm, 19×50 mm; Mobile Phase A: Water/0.1% FormicAcid; Mobile Phase B: MeCN/0.1% Formic Acid; Flow rate: 20 mL/min;Gradient: 2% B to 50% B in 7 min) to afford the title compound (10.3 mg,17% yield over 2 steps). ¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 11.21 (br s,1H), 9.01 (br s, 1H), 7.71-7.77 (m, 1H), 7.62-7.65 (m, 1H), 7.38 (d,J=8.5 Hz, 1H), 7.21 (d, J=8.5 Hz, 2H), 6.85 (d, J=8.5 Hz, 2H), 3.68 (s,3H), 3.54 (s, 2H), 3.48 (s, 2H), 3.24 (s, 3H). MS: (ES, m/z): 356[M+H]⁺.

Example 77—Preparation ofN-Hydroxy-4-(4-methoxybenzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide

Step-1: Methyl4-(4-methoxybenzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxylate

To a suspension of methyl4-(4-methoxybenzyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxylate(101 mg, 0.298 mmol, 1 equiv) in toluene (3 mL) was added borane-methylsulfide complex (164 μL, 0.328 mmol, 1.1 equiv). The mixture was heatedto reflux for 5 h, then cooled to room temperature. Methanol was addedand the reaction was stirred for 10 min at room temperature and then for15 min at reflux. The reaction mixture was concentrated and purified bysilica gel chromatography (Gradient 0-5% MeOH/CH₂Cl₂) to afford thetitle compound (83 mg, 85% yield). MS: (ES, m/z): 327 [M+H]⁺.

Step-2:N-Hydroxy-4-(4-methoxybenzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide

To a solution of methyl4-(4-methoxybenzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxylate(83 mg, 0.254 mmol, 1 equiv) in MeOH (250 μL) and THF (1 mL) was addedNH₂OH (50% in water, 1.33 mL, 21.6 mmol, 85 equiv) and aq. 2N NaOHsolution (254 μL, 0.509 mmol, 2 equiv). The reaction was stirred at roomtemperature for 3 h and was directly purified by Prep-HPLC (Column:Xbridge RP C18 OBD, 5 μm, 19×50 mm; Mobile Phase A: Water/0.1% FormicAcid; Mobile Phase B: MeCN/0.1% Formic Acid; Flow rate: 20 mL/min;Gradient: 2% B to 50% B in 7 min) to afford the title compound (11.3 mg,14% yield). ¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 8.39 (br s, 1H), 7.52-7.61(m, 2H), 7.41 (br d, J=8.2 Hz, 2H), 7 (d, J=8.2 Hz, 2H), 6.90 (d, J=8.2Hz, 1H), 4.20 (br d, J=9.1 Hz, 2H), 3.82 (s, 3H), 3.25-3.42 (m, 4H). MS:(ES, m/z): 328 [M+H]⁺.

Example 78—Preparation ofN-Hydroxy-4-(4-methoxybenzyl)-1-methyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide

Step-1: Methyl4-(4-methoxybenzyl)-1-methyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxylate

To a solution of methyl4-(4-methoxybenzyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxylate(60.7 mg, 0.186 mmol. 1 equiv) in MeCN (2 mL) was added Cs₂CO₃ (60.6 mg,0.186 mmol, 1 equiv), and methyl iodide (0.014 mL, 0.223 mmol, 1.2equiv). The reaction was stirred at room temperature for 7 h. Water wasadded to the reaction and the layers were separated. The aqueous layerwas extracted with CH₂Cl₂. The combined organic layers were dried overanhydrous Na₂SO₄, filtered, and concentrated. Purification by silica gelchromatography afforded the title compound (34 mg, 54% yield). MS: (ES,m/z): 341 [M+H]⁺.

Step-2:N-Hydroxy-4-(4-methoxybenzyl)-1-methyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide

To a solution of methyl4-(4-methoxybenzyl)-1-methyl-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxylate(34.1 mg, 0.100 mmol, 1 equiv) in MeOH (250 μL) and THF (1 mL) was addedNH₂OH (50% in water, 522 μL, 8.51 mmol, 85 equiv) and aq. 2N NaOHsolution (100 μL, 0.2 mmol, 2 equiv). The reaction was stirred at roomtemperature overnight and concentrated. Purification by Prep-HPLC(Column: Xbridge RP C18 OBD, 5 μm, 19×50 mm; Mobile Phase A: Water/0.05%formic acid; Mobile Phase B: MeCN/0.05% formic acid; Flow rate: 23mL/min; Gradient: 0% B to 35% B in 8 min; Detector, UV 254, 220 nm)afforded the title compound. MS: (ES, m/z): 342 [M+H]⁺.

Example 79—Preparation of2-benzyl-N-hydroxy-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine-8-carboxamide1,1-dioxide

Step-1: Methyl 4-bromo-3-(N-(2-hydroxyethyl)sulfamoyl)benzoate

Into a 100-mL round-bottom flask, was placed methyl4-bromo-3-(chlorosulfonyl)benzoate (100 mg, 0.32 mmol, 1 equiv), THF (2mL), water (0.5 mL), magnesium oxide (0.06 g) and 2-aminoethan-1-ol (22mg, 0.36 mmol, 1.1 equiv). The resulting mixture was stirred overnightat room temperature concentrated under vacuum. The residue was dilutedwith H₂O (50 mL). The resulting solution was extracted with EtOAc (3×50mL) and dried over anhydrous sodium sulfate. The solid was filtered out.The filtrate was concentrated under vacuum to afford the title compoundas a white solid (57 mg, 53% yield) which was used without furtherpurification. MS: (ES, m/z): 336 [M−H]⁻.

Step-2: Methyl 3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine-8-carboxylate1,1-dioxide

Into a 100-mL round-bottom flask, was placed methyl4-bromo-3-(N-(2-hydroxyethyl)sulfamoyl)benzoate (350 mg, 1.03 mmol, 1equiv), MeOH (2 mL), 1-methyl-2-pyrrolidinone (10 mL) and sodiummethylate (70 mg, 1.30 mmol, 1.25 equiv). The resulting mixture wasstirred 1 h at room temperature. To the above mixture was added CuI (16mg, 0.08 mmol, 0.08 equiv). The resulting solution was stirred overnightat 110° C. The resulting mixture was washed with H₂O (30 mL), extractedwith CH₂Cl₂ (2×30 mL) and dried over anhydrous sodium sulfate. The solidwas filtered. The filtrate was concentrated and the residue was purifiedby silica gel chromatography (EtOAc/pet. ether, 1:3) to afford the titlecompound as a yellow oil (250 mg, 93% yield). MS: (ES, m/z): 256 [M−H]⁻.

Step-3: Methyl2-benzyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine-8-carboxylate1,1-dioxide

Into a 100-mL round-bottom flask, was placed methyl3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine-8-carboxylate 1,1-dioxide(50 mg, 0.19 mmol, 1 equiv), DMF (3 mL), sodium hydride (9 mg, 0.38mmol, 1.9 equiv), (bromomethyl)benzene (48 mg, 0.28 mmol, 1.4 equiv).The resulting mixture was stirred for 2 h at room temperature and thendiluted with H₂O (20 mL). The resulting solution was extracted withEtOAc (2×40 mL), washed with H₂O (2×30 mL), and dried over anhydroussodium sulfate. The solid was filtered out. The filtrate wasconcentrated under vacuum to afford the title compound as a yellow oil(87 mg) which was used without further purification.

Step-4:2-Benzyl-N-hydroxy-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine-8-carboxamide1,1-dioxide

Into a 100-mL round-bottom flask, was placed methyl2-benzyl-3,4-dihydro-2H-benzo[b][1,4,5]oxathiazepine-8-carboxylate1,1-dioxide (87 mg, 0.25 mmol, 1 equiv), THFE (2 mL), MeOH (0.5 mL), aq.1N NaOH (0.4 mL) and NH₂OH (50% in water, 800 mg, 24.22 mmol). Theresulting solution was stirred for 1 h at room temperature. The pH valueof the solution was adjusted to 3 with 1N HCl. The crude product waspurified by Prep-HPLC (Column: Xbridge Prep C18 OBD, 5 μm, 19×50 mm;Mobile Phase A: Water/0.3% formic acid; Mobile Phase B: MeCN; Flow rate:23 mL/min; Gradient: 18% B to 59% B in 6 min, up to 100% B in 0.1 min,hold 0.9 min; Detector, UV 254, 220 nm) to afford the title compound asa white solid (9.6 mg, 11% yield). ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm):8.18 (d, 1H), 7.80-7.97 (q, 1H), 7.39-7.30 (m, 6H), 4.29-4.27 (t, 2H,J=4.0 Hz), 4.20 (s, 2H), 3.56-3.54 (t, 2H, J=4.4 Hz). MS: (ES, m/z):349[M+H]⁺.

TABLE 35 The following compound was prepared according to the method ofExample 79. Found Structure M + H ¹H-NMR (400 MHz, DMSO-d₆) δ(ppm)

(ES, m/z): 349 [M + H]⁺ 11.40 (s, 1H), 9.30 (s, 1H), 7.86 (d, 1H),7.72-7.69 (m, 1H), 7.60 (d, 1H), 7.39-7.31 (m, 5H), 4.28-4.18 (m, 4H),3.55-3.53 (t, 2H, J = 4.0 Hz)

Example 80—Preparation ofN8-hydroxy-N4-(4-methoxyphenyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide

Step-1: Methyl4-((4-methoxyphenyl)carbamoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

A 2 mL reaction vial was charged with methyl2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (0.2 M in1,2-dichloroethane, 150 μL, 30 μmol) and triethylamine (neat, 10 μL, 71μmol). 1-Isocyanato-4-methoxybenzene (0.2 M in dioxane, 195 μL, 39 μmol)was added and the vial was sealed and shaken at room temperatureovernight. The reaction mixture was diluted with brine (500 μL) andextracted with EtOAc (2×500 μL). The combined organic layers wereevaporated to dryness under reduced pressure.

Step-2:N8-Hydroxy-N4-(4-methoxyphenyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide

Mixed solvent of THF/MeOH (3:1, 180 μL) was added to the vial containingmethyl4-((4-methoxyphenyl)carbamoyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylateand it was shaken at 50° C. for 15 min to dissolve the residue. NH₂OH(50% in water, 125 μL) was added, followed by aq. 1N NaOH (85 μL) andthe vial was sealed and shaken at room temperature overnight. Thesolvent was evaporated under reduce pressure and the residue wasdissolved in DMSO (500 μL), then purified by HPLC to afford the titlecompound (9.3 mg, 87% yield). MS: (ES, m/z): 358 [M+H]⁺.

TABLE 36 The following compound was prepared by the parallel synthesismethod of Example 80. Found Structure M + H (ES)

358

324

342

Example 81—Preparation ofN-hydroxy-4-((4-methoxyphenyl)sulfonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl4-((4-methoxyphenyl)sulfonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

A 2 mL reaction vial was charged with methyl2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (0.2 M in1,2-dichloroethane, 150 μL, 30 μmol) and Et₃N (neat, 10 μL, 71 μmol).4-Methoxybenzenesulfonyl chloride (0.2 M in 1,2-dichloroethane, 195 μL,39 μmol) was added and the vial was sealed and shaken at roomtemperature overnight. The reaction mixture was diluted with brine (500μL) and extracted with EtOAc (2×500 μL). The combined organic layerswere evaporated to dryness under reduced pressure.

Step-2:N-Hydroxy-4-((4-methoxyphenyl)sulfonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Mixed solvent of THF/MeOH (3:1, 180 μL) was added to the vial containingmethyl4-((4-methoxyphenyl)sulfonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylateand it was shaken at 50° C. for 15 min to dissolve the residue. NH₂OH(50% in water, 125 μL) was added followed by aq. 1N NaOH (85 μL) and thevial was sealed and shaken at room temperature overnight. The solventwas evaporated under reduce pressure and the residue was dissolved inDMSO (500 μL) then purified by HPLC to afford the title compound (9.1mg, 80% yield). MS: (ES, m/z): 379 [M+H]⁺.

TABLE 37 The following compound was prepared by the parallel synthesismethod of Example 81. Structure Found M + H (ES)

379

315

345

301

381

Example 82—Preparation of4-((1H-benzo[d]imidazol-2-yl)methyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl4-((1H-benzo[d]imidazol-2-yl)methyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

A 2 mL reaction vial was charged with methyl2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (0.2M inN,N-dimethylacetamide, 200 μL, 40 μmol) and2-(chloromethyl)-1H-benzo[d]imidazole (0.2M in N,N-dimethylacetamide,200 μL, 40 μmol). Solid K₂CO₃ (22 mg, 160 μmol) was added and the vialwas sealed and shaken at room temperature overnight. The reactionmixture was diluted with brine (500 μL) and extracted with EtOAc (2×500μL). The combined organic layers were evaporated to dryness underreduced pressure.

Step-2:4-((1H-benzo[d]imidazol-2-yl)methyl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Mixed solvent of THF/MeOH (3:1, 180 μL) was added to the vial containingmethyl4-((1H-benzo[d]imidazol-2-yl)methyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylateand it was shaken at 50° C. for 15 min to dissolve the residue. NH₂OH(50% in water, 125 μL) was added followed by aq. 1N NaOH (75 μL) and thevial was sealed and shaken at room temperature overnight. The solventwas evaporated under reduce pressure and the residue was dissolved inDMSO (500 μL) then purified by HPLC to afford the title compound (9.8mg, 72% yield). MS: (ES, m/z): 339 [M+H]⁺.

TABLE 38 The following compounds were prepared by the parallel synthesismethod of Example 82. Structure Found M + H (ES)

339

397

397

329

295

345

350

321

251

265

279

291

343

343

329

277

331

319

336

281

305

307

291

Example 83—Preparation of4-(1H-benzo[d]imidazol-2-yl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl4-(1H-benzo[d]imidazol-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

A 2 mL reaction vial was charged with methyl2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate (0.2M in1-butanol, 200 μL, 40 μmol) and 2-bromo-1H-benzo[d]imidazole (0.2M in1-butanol, 240 μL, 48 μmol). Solid KH₂PO₄ (21.8 mg, 160 μmol) was addedand the vial was sealed and shaken at 110° C. overnight. The solvent wasremoved under reduced pressure and to the residue is added brine (500μL). The mixture was extracted with EtOAc (2×500 μL) and the combinedorganic layers were evaporated to dryness under reduced pressure.

Step-2:4-(1H-benzo[d]imidazol-2-yl)-N-hydroxy-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Mixed solvent of THF/MeOH (3:1, 180 μL) was added to the vial containingmethyl4-(1H-benzo[d]imidazol-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylateand it was shaken at 50° C. for 15 min to dissolve the residue. NH₂OH(50% in water, 125 μL) was added followed by aq. 1N NaOH (85 μL) and thevial was sealed and shaken at room temperature overnight. The solventwas evaporated under reduce pressure and the residue was dissolved inDMSO (500 μL) then purified by HPLC to afford the title compound (7.0mg, 54% yield). MS: (ES, m/z): 325 [M+H].

TABLE 39 The following compounds were prepared by the parallel synthesismethod of Example 83. Structure Found M + H (ES)

325

383

383

Example 84—Preparation ofN-hydroxy-4-((5-isopropylpyridin-2-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide

Step-1: Methyl4-(4-isopropylbenzyl)-2-oxo-2,3,4,5-tetrahydro-H-benzo[e][1,4]diazepine-7-carboxylate

A 2 mL reaction vial was charged with methyl2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxylate (0.2 Min N,N-dimethylacetamide, 150 μL, 30 μmol) and5-isopropylpicolinaldehyde (0.2 M in 1,2-dichloroethane, 225 μL, 45μmol). The vial was sealed and shaken at room temperature for 1 h.Sodium triacetoxyborohydride (0.2M in 1,2-dichloroethane, 500 μL, 100μmol) was added and the vial was shaken at room temperature overnight.Half volume of the solvent was removed under reduced pressure. Thereaction mixture was diluted with 1N NaOH in brine (500 μL) andextracted with EtOAc (2×500 μL). The combined organic layers wereevaporated to dryness under reduced pressure.

Step-2:N-hydroxy-4-((5-isopropylpyridin-2-yl)methyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide

Mixed solvent of THF/MeOH (3:1, 180 μL) was added to the vial containingmethyl4-(4-isopropylbenzyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxylateand it was shaken at 50° C. for 15 min to dissolve the residue. NH₂OH(50% in water, 125 μL) was added followed by aq. 1N NaOH (85 μL) and thevial was sealed and shaken at room temperature overnight. The solventwas evaporated under reduce pressure and the residue was dissolved inDMSO (500 μL) then purified by HPLC to afford the title compound (1.6mg, 15% yield). MS: (ES, m/z): 355 [M+H]⁺.

TABLE 40 The following compounds were prepared by the parallel synthesismethod of Example 84. Structure Found M + H (ES)

313

313

319

370

396

404

404

396

312

354

346

348

348

380

360

346

392

361

377

362

398

352

396

389

378

337

314

362

397

369

313

316

361

352

276

306

347

346

384

395

330

330

330

330

Example 85—Preparation ofN-hydroxy-4-(2-methylpiperidine-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl4-(2-methylpiperidine-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

A 2-mL reaction vial was charged with triphosgene (0.1M in MeCN, 200 μL,20 mol), methyl 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(0.2 M in MeCN, 250 μL, 50 μmol) and triethylamine (neat, 14 μL, 100μmol). The mixture was stirred for 20 min. To this mixture was thenadded 2-methylpiperidine (neat, 24.8 mg, 250 μmol) and the resultingmixture was stirred at room temperature for 2 h, after which time it wasdiluted with sat aq NaHCO₃ (500 μL) and extracted with EtOAc (2×500 μL).The combined organic layers were evaporated to dryness under reducedpressure.

Step-2:N-Hydroxy-4-(2-methylpiperidine-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Mixed solvent of THF/MeOH (3:1, 180 μL) was added to the vial containingmethyl4-(2-methylpiperidine-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylateand it was shaken at 50° C. for 15 min to dissolve the residue. NH₂OH(50% in water, 125 μL) was added followed by aq. 1N NaOH (85 μL) and thevial was sealed and shaken at room temperature overnight. The solventwas evaporated under reduce pressure and the residue was dissolved inDMSO (500 μL) then purified by HPLC to afford the title compound (7.1mg, 42.6% yield). MS: (ES, m/z): 334 [M+H]⁺.

TABLE 41 The following compounds were prepared by the parallel synthesismethod Example 85. Found M + H Structure (ES)

306

322

335

320

336

368

349

348

350

354

336

350

334

338

356

Example 86—Preparation of(S)—N8-hydroxy-N4,N4,3-trimethyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide

Step-1: Methyl(S)-4-(dimethylcarbamoyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

A 2-mL reaction vial was charged with dimethylcarbamic chloride (0.2M indichloroethane, 400 μL, 80 μmol), methyl(S)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(0.2M in dichloroethane, 200 μL, 40 μmol) and triethylamine (neat, 11μL, 80 μmol). The reaction was stirred at room temperature for 2 h,after which time it was diluted with brine (500 μL) and extracted withEtOAc (2×500 μL). The combined organic layers were evaporated to drynessunder reduced pressure.

Step-2:(S)—N8-hydroxy-N4,N4,3-trimethyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide

Mixed solvent of THF/MeOH (3:1, 180 μL) was added to the vial containingmethyl(S)-4-(dimethylcarbamoyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylateand it was shaken at 50° C. for 15 min to dissolve the residue. NH₂OH(50% in water, 125 μL) was added followed by aq. 1N NaOH (85 μL) and thevial was sealed and shaken at room temperature overnight. The solventwas evaporated under reduce pressure and the residue was dissolved inDMSO (500 μL) then purified by HPLC to afford the title compound. MS:(ES, m/z): 294 [M+H]⁺.

TABLE 42 The following compound was prepared by the parallel synthesismethod of Example 86. Structure Found M + H (ES)

281

Example 87—Preparation of(S)—N-hydroxy-3-methyl-4-(3-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-3-methyl-4-(3-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

A 2-mL reaction vial was charged with dimethylcarbamic chloride (0.2M indichloroethane, 400 μL, 80 μmol), methyl(S)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(0.2M in dichloroethane, 150 μL, 30 μmol), triethylamine (neat, 12.5 μL,90 μmol), Cu(OAc)₂ (150 μL 0.4M in DMSO, 60 μmol), and(3-(trifluoromethyl)phenyl)boronic acid (300 μL, 0.2M in dichloroethane,60 μmol). The reaction was stirred at room temperature for 2 days, afterwhich time the solvent was removed under vacuum. The residual solutionwas diluted with brine (500 μL) and NH₄OH (100 μL), then extracted withEtOAc (2×500 μL). The combined organic layers were evaporated to drynessunder reduced pressure.

Step-2:(S)—N-Hydroxy-3-methyl-4-(3-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Mixed solvent of THF/MeOH (3:1, 180 μL) was added to the vial containingmethyl(S)-3-methyl-4-(3-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylateand it was shaken at 50° C. for 15 min to dissolve the residue. NH₂OH(50% in water, 125 μL) was added followed by aq. 1N NaOH (85 μL) and thevial was sealed and shaken at room temperature overnight. The solventwas evaporated under reduce pressure and the residue was dissolved inDMSO (500 μL) then purified by HPLC to afford the title compound (0.4mg, 3.64% yield). MS: (ES, m/z): 367 [M+H]⁺.

TABLE 43 The following compounds were prepared by the parallel synthesismethod of Example 87. Found M + H Structure (ES)

383

334

Example 88—Preparation of(S)-4-(2-chlorophenyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Step-1: Methyl(S)-4-(2-chlorophenyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate

Under N₂, to a 2-mL reaction vial were charged methyl(S)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylate(0.2M in dioxane, 150 μL, 30 μmol), 1-bromo-2-chlorobenzene (0.2M intoluene, 300 μL, 60 μmol), Xphos Pd G₂ (3 μmol, 24 mg) and sodiumtert-butoxide (60 μmol, 5.7 mg), then the vial was sealed and heated at150° C. in microwave for 90 min. The solvent was removed under vacuum.The residual solution was diluted with brine (500 μL) and extracted withEtOAc (2×500 μL). The combined organic layers were evaporated to drynessunder reduced pressure.

Step-2:(S)-4-(2-Chlorophenyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide

Mixed solvent of THF/MeOH (3:1, 180 μL) was added to the vial containingmethyl(S)-4-(2-chlorophenyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxylateand it was shaken at 50° C. for 15 min to dissolve the residue. NH₂OH(50% in water, 125 μL) was added followed by aq. 1N NaOH (85 μL) and thevial was sealed and shaken at room temperature overnight. The solventwas evaporated under reduce pressure and the residue was dissolved inDMSO (500 μL) then purified by HPLC to afford the title compound (0.4mg, 4.01% yield). MS: (ES, m/z): 334 [M+H]⁺.

TABLE 44 The following compounds were prepared by the parallel synthesismethod of Example 88. Found Structure M + H (ES)

317

Example 89—In Vitro Histone Deacetylase Assay

The enzymatic HDAC6 assay was performed using electrophoretic mobilityshift assay. Full length human recombinant HDAC6 protein was expressedin baculoviral system and purified by affinity chromatography. Theenzymatic reactions were assembled in 384 well plates in a total volumeof 25 μL in a reaction buffer composing: 100 mM HEPES, pH7.5, 25 mM KCl,0.1% bovine serum albumin, 0.01% Triton X-100, 1% DMSO (from compounds)2 μM of the fluorescently labeled peptide substrate and enzyme. Theenzyme was added at a final concentration of 1 nM. The peptide substrateRHKK(Ac)—NH2 was used. The compounds were tested at 12 concentrationsspaced by 3× dilution intervals. Negative control samples (0%-inhibitionin the absence of inhibitor) and positive control samples(100%-inhibition) were assembled in replicates of four in each assayplate. The reactions were incubated at 25° C. and quenched by theaddition of 45 μL of termination buffer (100 mM HEPES, pH 7.5, 0.01%Triton X-100, 0.05% SDS).

The terminated assay plates were analyzed on LabChip® 3000 microfluidicelectrophoresis instrument (Perkin Elmer/Caliper Life Sciences). Thefluorescence intensity of the electrophoretically separatedde-acetylated product and substrate peptide was measured. Activity ineach sample was determined as the product to sum ratio (PSR): P/(S+P),where P is the peak height of the product peptide and S is the peakheight of the substrate peptide. Percent inhibition (Pinh) is determinedusing the following equation:Pinh=(PSR0%−PSRinh)/(PSR0%−PSR100%)*100,where PSRinh is the product sum ratio in the presence of inhibitor,PSR0% is the average product sum ration in the absence of inhibitor andPSR100% is the average product sum ratio in 100%-inhibition controlsamples. The IC₅₀ values of inhibitors were determined by fitting the%-inhibition curves with 4 parameter dose-response model using XLfit 4software.

As set forth in Table 45, below, IC₅₀ values are defined as follows:IC50≤0.1 μM (+++); IC50>0.1 μM and ≤0.5 μM (++); IC50>0.5 μM (+).

TABLE 45 Inhibitory Concentration (IC₅₀) Values for RepresentativeCompounds against HDAC6. Activity NAME Range4-(1,3-benzoxazol-2-yl)-N-hydroxy-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide+++4-[1-(cyclohexylmethyl)-1H-1,3-benzodiazol-2-yl]-N-hydroxy-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide++4-(1,3-benzothiazol-2-yl)-N-hydroxy-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide++4-(cyclohexylmethyl)-N-hydroxy-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide++N-hydroxy-4-phenyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide +4-[4-cyano-3-(trifluoromethyl)phenyl]-N-hydroxy-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide++4-(3,4-dichlorophenyl)-N-hydroxy-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide++N-hydroxy-4-(pyridin-2-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide++N-hydroxy-4-(pyridin-3-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide++N-hydroxy-4-(pyridin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide +N-hydroxy-4-(4-methylphenyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide++N-hydroxy-4-(piperidine-1-carbonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide+++ 4-methoxyphenyl8-(hydroxycarbamoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-4-carboxylate+++ cyclohexyl8-(hydroxycarbamoyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-4-carboxylate+++N-hydroxy-4-(piperidine-1-sulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide+++N8-hydroxy-N4-methyl-N4-phenyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-4,8-dicarboxamide +4-cyclohexyl-N-hydroxy-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide +4-[2-(dimethylamino)ethyl]-N-hydroxy-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide +N-hydroxy-4-(2-methoxyethyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide++N-hydroxy-4-[1-(oxan-4-ylmethyl)-1H-1,3-benzodiazol-2-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide++ N-hydroxy-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide ++N-hydroxy-4-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide ++(2R)-N-hydroxy-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide +(2R)-N8-hydroxy-N4-(4-methoxyphenyl)-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-4,8-dicarboxamide++(2R)-N-hydroxy-4-(4-methoxybenzenesulfonyl)-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide++(2R)-N-hydroxy-4-[(4-methoxyphenyl)methyl]-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide++(2R)-N-hydroxy-2-methyl-4-phenyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide++(2R)-N-hydroxy-2,4-dimethyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide +(2S)-N-hydroxy-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide++(2S)-N8-hydroxy-N4-(4-methoxyphenyl)-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-4,8-dicarboxamide+++(2S)-N-hydroxy-4-(4-methoxybenzenesulfonyl)-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide +(2S)-N-hydroxy-2-methyl-4-phenyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide +(2S)-N-hydroxy-2,4-dimethyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide +(2S)-N-hydroxy-4-[(4-methoxyphenyl)methyl]-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide++N-hydroxy-4-[(4-methoxyphenyl)methyl]-3,3-dimethyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide++N-hydroxy-3,3-dimethyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide+++N-hydroxy-3,3,4-trimethyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide+++(3R)-N-hydroxy-4-[(4-methoxyphenyl)methyl]-3-(propan-2-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide+++(3R)-N-hydroxy-4-phenyl-3-(propan-2-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide++(3R)-N8-hydroxy-N4-(4-methoxyphenyl)-3-(propan-2-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-4,8-dicarboxamide++(3R)-N-hydroxy-3-(propan-2-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide+++(3R)-N-hydroxy-4-methyl-3-(propan-2-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide+++(3S)-N-hydroxy-4-[(4-methoxyphenyl)methyl]-3-(propan-2-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide+++(3S)-N-hydroxy-4-phenyl-3-(propan-2-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide+++(3S)-N8-hydroxy-N4-(4-methoxyphenyl)-3-(propan-2-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-4,8-dicarboxamide+++(3S)-N-hydroxy-3-(propan-2-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide+++(3S)-N-hydroxy-4-methyl-3-(propan-2-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide+++(3R)-N-hydroxy-3-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide++(3R)-N-hydroxy-3,4-dimethyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide+++(3R)-N8-hydroxy-N4-(4-methoxyphenyl)-3-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-4,8-dicarboxamide++(3R)-N-hydroxy-4-(4-methoxybenzenesulfonyl)-3-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide +(3R)-N-hydroxy-4-[(4-methoxyphenyl)methyl]-3-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide+++(3R)-N-hydroxy-3-methyl-4-phenyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide++(3S)-N8-hydroxy-N4-(4-methoxyphenyl)-3-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-4,8-dicarboxamide+++(3S)-N-hydroxy-4-(4-methoxybenzenesulfonyl)-3-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide++(3S)-N-hydroxy-4-[(4-methoxyphenyl)methyl]-3-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide+++(3S)-N-hydroxy-3-methyl-4-phenyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide+++(3S)-N-hydroxy-3-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide++(3S)-N-hydroxy-3,4-dimethyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide++(5R/5S)-N-hydroxy-4-[(4-methoxyphenyl)methyl]-5-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-7-carboxamide, +(5S/5R)-N-hydroxy-4-[(4-methoxyphenyl)methyl]-5-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-7-carboxamide, +N8-hydroxy-N4-(4-methoxyphenyl)-2H,3H,4H,5H-pyrido[2,3-f][1,4]oxazepine-4,8-dicarboxamide+++N-hydroxy-4-(4-methoxybenzenesulfonyl)-2H,3H,4H,5H-pyrido[2,3-f][1,4]oxazepine-8-carboxamide++N-hydroxy-4-[(4-methoxyphenyl)methyl]-2H,3H,4H,5H-pyrido[2,3-f][1,4]oxazepine-8-carboxamide++N8-hydroxy-N4-(4-methoxyphenyl)-2H,3H,4H,5H-pyrido[3,2-f][1,4]oxazepine-4,8-dicarboxamide +N-hydroxy-4-(4-methoxybenzenesulfonyl)-2H,3H,4H,5H-pyrido[3,2-f][1,4]oxazepine-8-carboxamide +N-hydroxy-4-[(4-methoxyphenyl)methyl]-2H,3H,4H,5H-pyrido[3,2-f][1,4]oxazepine-8-carboxamide +N-hydroxy-4-[(4-methoxyphenyl)methyl]-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide++N-hydroxy-4-[2-(4-methoxyphenyl)ethyl]-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide++N-hydroxy-4-[(4-methoxyphenyl)methyl]-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepine-7-carboxamide +N-hydroxy-4-[2-(4-methoxyphenyl)ethyl]-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepine-7-carboxamide++N-hydroxy-4-[2-(4-methoxyphenyl)ethyl]-2-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-8-carboxamide +4-(1H-1,3-benzodiazol-2-ylmethyl)-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-8-carboxamide++4-(1H-1,3-benzodiazol-2-ylmethyl)-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide+++N-hydroxy-4-[2-(4-methoxyphenyl)ethyl]-2-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide++N-hydroxy-2-oxo-4-(1-phenylethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide+++N-hydroxy-4-[(4-methoxyphenyl)methyl]-2-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide++N-hydroxy-4-(4-methoxybenzenesulfonyl)-2-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide +N-hydroxy-2-oxo-4-phenyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide +N-hydroxy-4-[(4-methoxyphenyl)methyl]-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide +N-hydroxy-4-[(4-methoxyphenyl)methyl]-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide +N-hydroxy-4-[(4-methoxyphenyl)methyl]-1-methyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide +2-benzyl-N-hydroxy-1,1-dioxo-3,4-dihydro-2H-5,1λ⁶,2-benzoxathiazepine-8-carboxamide++2-benzyl-N-hydroxy-1,1-dioxo-3,4-dihydro-2H-5,1λ⁶,2-benzoxathiazepine-7-carboxamide +N8-hydroxy-N4-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-4,8-dicarboxamide++N7-hydroxy-N4-(4-methoxyphenyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-4,7-dicarboxamide +N-hydroxy-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide++N-hydroxy-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1,4-benzoxazepine-7-carboxamide++4-(1H-1,3-benzodiazol-2-ylmethyl)-N-hydroxy-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide+++4-(1H-1,3-benzodiazol-2-ylmethyl)-N-hydroxy-2,3,4,5-tetrahydro-1,4-benzoxazepine-7-carboxamide +N-hydroxy-4-{[1-(2-methoxyethyl)-1H-1,3-benzodiazol-2-yl]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide++N-hydroxy-4-{[1-(2-methoxyethyl)-1H-1,3-benzodiazol-2-yl]methyl}-2,3,4,5-tetrahydro-1,4-benzoxazepine-7-carboxamide +N-hydroxy-4-[2-(4-methoxyphenyl)ethyl]-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide++N-hydroxy-4-[2-(4-methoxyphenyl)ethyl]-2,3,4,5-tetrahydro-1,4-benzoxazepine-7-carboxamide +N-hydroxy-4-[(4-methoxyphenyl)methyl]-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide++N-hydroxy-4-[(4-methoxyphenyl)methyl]-2,3,4,5-tetrahydro-1,4-benzoxazepine-7-carboxamide +4-(1H-1,3-benzodiazol-2-yl)-N-hydroxy-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide+++4-(1H-1,3-benzodiazol-2-yl)-N-hydroxy-2,3,4,5-tetrahydro-1,4-benzoxazepine-7-carboxamide++N-hydroxy-4-[1-(2-methoxyethyl)-1H-1,3-benzodiazol-2-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide+++N-hydroxy-4-[1-(2-methoxyethyl)-1H-1,3-benzodiazol-2-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepine-7-carboxamide++N-hydroxy-2-oxo-4-{[5-(propan-2-yl)pyridin-2-yl]methyl}-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide++N-hydroxy-2-oxo-4-(pyridin-4-ylmethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide++N-hydroxy-2-oxo-4-(pyridin-2-ylmethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide +N-hydroxy-2-oxo-4-(1,3-thiazol-2-ylmethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide +N-hydroxy-2-oxo-4-{[4-(propan-2-yloxy)phenyl]methyl}-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide+++N-hydroxy-2-oxo-4-{[4-(trifluoromethoxy)phenyl]methyl}-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide++N-hydroxy-2-oxo-4-[(3-phenoxyphenyl)methyl]-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide++N-hydroxy-2-oxo-4-[(4-phenoxyphenyl)methyl]-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide+++N-hydroxy-2-oxo-4-{[3-(trifluoromethoxy)phenyl]methyl}-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide++N-hydroxy-2-oxo-4-{[2-(trifluoromethoxy)phenyl]methyl}-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide+++N-hydroxy-2-oxo-4-{[4-(pyridin-2-yl)phenyl]methyl}-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide+++N-hydroxy-2-oxo-4-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide+++4-[(4-cyanophenyl)methyl]-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide++N-hydroxy-2-oxo-4-(pyrimidin-5-ylmethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide +N-hydroxy-4-(naphthalen-1-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide+++4-{[2-(3-fluorophenyl)-1,3-oxazol-4-yl]methyl}-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide+++4-({3-[(dimethylamino)methyl]phenyl}methyl)-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide +4-benzyl-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide++N-hydroxy-2-oxo-4-{[4-(propan-2-yl)phenyl]methyl}-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide+++4-[(4-chlorophenyl)methyl]-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide+++4-[(2,5-difluorophenyl)methyl]-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide++4-[(3,5-difluorophenyl)methyl]-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide++4-[(3,5-dichlorophenyl)methyl]-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide+++4-[(2-fluoro-4-methoxyphenyl)methyl]-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide+++4-[(2-chlorophenyl)methyl]-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide++4-[(2,2-difluoro-2H-1,3-benzodioxol-4-yl)methyl]-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide+++N-hydroxy-2-oxo-4-(pyridin-3-ylmethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide++N-hydroxy-4-[(1-methyl-1H-imidazol-2-yl)methyl]-2-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide++4-[(1-acetylpiperidin-3-yl)methyl]-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide +N-hydroxy-4-{imidazo[1,2-a]pyridin-2-ylmethyl}-2-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide+++4-(cyclopropylmethyl)-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide++N-hydroxy-2-oxo-4-(oxolan-3-ylmethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide +4-[(dimethyl-1,3-thiazol-2-yl)methyl]-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide++4-[(3-chlorophenyl)methyl]-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide++4-{[4-(tert-butoxy)phenyl]methyl}-N-hydroxy-2-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide++N-hydroxy-2-oxo-4-{[1-(propan-2-yl)piperidin-4-yl]methyl}-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide +N-hydroxy-2-oxo-4-{[4-(1H-pyrrol-1-yl)phenyl]methyl}-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide+++N-hydroxy-4-(naphthalen-2-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide+++N-hydroxy-4-{[2-(morpholin-4-yl)pyridin-4-yl]methyl}-2-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide++N-hydroxy-4-{imidazo[1,2-a]pyridin-7-ylmethyl}-2-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide++N-hydroxy-2-oxo-4-{[4-(1,3-thiazol-2-yl)phenyl]methyl}-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-7-carboxamide+++N-hydroxy-4-[(6-methoxypyridin-3-yl)methyl]-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide++N-hydroxy-4-[(6-methoxypyridin-3-yl)methyl]-2,3,4,5-tetrahydro-1,4-benzoxazepine-7-carboxamide +N-hydroxy-4-[(5-methoxypyridin-2-yl)methyl]-2,3,4,5-tetrahydro-1,4-benzoxazepine-8-carboxamide++N-hydroxy-4-[(5-methoxypyridin-2-yl)methyl]-2,3,4,5-tetrahydro-1,4-benzoxazepine-7-carboxamide +(R)-N8-hydroxy-2-isopropyl-N4-(4-methoxyphenyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide +(R)-N8-hydroxy-2-(methoxymethyl)-N4-(4-methoxyphenyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide++(S)-N8-hydroxy-2-(methoxymethyl)-N4-(4-methoxyphenyl)-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide++(R)-N8-hydroxy-N4-(4-methoxyphenyl)-2-phenyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide++(S)-N8-hydroxy-N4-(4-methoxyphenyl)-2-phenyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide+++N-hydroxy-4-methyl-4,5-dihydro-2H-spiro[benzo[f][1,4]oxazepine-3,1′-cyclopropane]-8-carboxamide+++N-hydroxy-4-phenyl-4,5-dihydro-2H-spiro[benzo[f][1,4]oxazepine-3,1′-cyclopropane]-8-carboxamide++N-hydroxy-4-(4-methoxybenzyl)-4,5-dihydro-2H-spiro[benzo[f][1,4]oxazepine-3,1′-cyclopropane]-8-carboxamide+++(S)-3-ethyl-N-hydroxy-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(S)-3-ethyl-N-hydroxy-4-(4-methoxybenzyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(S)-3-ethyl-N-hydroxy-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(S)-3-ethyl-N-hydroxy-4-(o-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(S)-N-hydroxy-3-isopropyl-4-(pyridin-3-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(S)-N-hydroxy-3-isopropyl-4-(pyridin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(S)-N-hydroxy-3-isopropyl-4-(pyridin-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide +(S)-N-hydroxy-3-methyl-4-(o-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(S)-N-hydroxy-4-(2-methoxyphenyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(S)-N-hydroxy-3-methyl-4-(pyridin-2-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(S)-N-hydroxy-3-methyl-4-(pyrrolidine-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(S)-N-hydroxy-3-methyl-4-(morpholine-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(S)-N-hydroxy-4-(isoindoline-2-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(S)-N-hydroxy-4-(4-methoxypiperidine-1-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(S)-N-hydroxy-3-methyl-4-(4-methylpiperazine-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide++(3S)-N-hydroxy-3-methyl-4-(2-methylpiperidine-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(3S)-N-hydroxy-3-methyl-4-(3-methylmorpholine-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(S)-N-hydroxy-3-methyl-4-(oxetan-3-ylmethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(S)-4-(4-fluorophenyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(S)-4-(3-fluorophenyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(S)-N-hydroxy-3-methyl-4-(4-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide++ methyl(S)-8-(hydroxycarbarmoyl)-3-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate+++ isopropyl(S)-8-(hydroxycarbamoyl)-3-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate+++(S)-N-hydroxy-3-methyl-4-(methylsulfonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(S)-4-(ethylsulfonyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(S)-N8-hydroxy-N4,N4,3-trimethyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide+++(S)-N-hydroxy-4-((2-methoxyethyl)sulfonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide++(S)-N8-hydroxy-N4-(2-methoxyethyl)-3-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide+++(S)-N8-hydroxy-3-methyl-N4-phenyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide+++(S)-N-hydroxy-3-methyl-4-(piperidine-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(3S)-N8-hydroxy-N4-(2-methoxyethyl)-N4,3-dimethyl-2,3,7,8-tetrahydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide+++(S)-N-hydroxy-3-methyl-4-(pyridin-3-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(S)-N-hydroxy-3-methyl-4-(pyridin-4-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide++(S)-N-hydroxy-4-(3-methoxypropyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide++(3S)-4-(1-(4-fluorophenyl)ethyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide++(S)-N-hydroxy-3-methyl-4-(3-morpholinopropyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide++(3S)-N-hydroxy-3-methyl-4-(2-(tetrahydrofuran-2-yl)ethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(S)-4-ethyl-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide++(S)-N-hydroxy-4-isopropyl-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide +(S)-N-hydroxy-4-isobutyl-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(S)-4-(cyclobutylmethyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(S)-4-(cyclopropylmethyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(S)-4-(4-fluorobenzyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(S)-4-(cyclohexylmethyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(S)-N-hydroxy-3-methyl-4-(2-morpholinoethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide++(S)-N-hydroxy-4-(2-methoxyethyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(S)-4-(cyclopentylmethyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(3S)-N-hydroxy-3-methyl-4-((tetrahydrofuran-2-yl)methyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(S)-4-cyclopentyl-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide++(S)-4-((4-fluorophenyl)sulfonyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide++ cyclopentyl(S)-8-(hydroxycarbamoyl)-3-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate+++ cyclohexyl(S)-8-(hydroxycarbamoyl)-3-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate+++(S)-N8-hydroxy-N4,3-dimethyl-N4-phenyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide++ ethyl(S)-8-(hydroxycarbamoyl)-3-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate+++ cyclobutyl(S)-8-(hydroxycarbamoyl)-3-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate+++ tetrahydro-2H-pyran-4-yl(S)-8-(hydroxycarbamoyl)-3-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate+++ 4-fluorophenyl(S)-8-(hydroxycarbarmoyl)-3-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carboxylate+++(S)-N-hydroxy-3-methyl-4-(oxetan-3-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide +(R)-N-hydroxy-3-(methoxymethyl)-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(R)-N-hydroxy-4-(4-methoxybenzyl)-3-(methoxymethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(R)-N-hydroxy-3-(methoxymethyl)-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide++(R)-N-hydroxy-3-(methoxymethyl)-4-(o-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(S)-N-hydroxy-3-(methoxymethyl)-4-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(S)-N-hydroxy-4-(4-methoxybenzyl)-3-(methoxymethyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(S)-N-hydroxy-3-(methoxymethyl)-4-phenyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(S)-N-hydroxy-3-(methoxymethyl)-4-(o-tolyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++N-hydroxy-4-(pyrrolidine-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++N-hydroxy-4-(morpholine-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide++N-hydroxy-4-(4-methylpiperazine-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide +N-hydroxy-4-(4-methoxypiperidine-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide++N-hydroxy-4-(isoindoline-2-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++N-hydroxy-4-(2-methylpiperidine-1-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++N-hydroxy-4-(3-methylmorpholine-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide++(R)-N-hydroxy-4-(4-methoxybenzyl)-5-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide +(S)-N-hydroxy-4-(4-methoxybenzyl)-5-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide++(S)-N-hydroxy-3-methyl-4-(3-(trifluoromethyl)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide++(S)-N-hydroxy-3-methyl-4-(4-(trifluoromethoxy)phenyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide++(S)-4-(4-chlorophenyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(S)-4-(2-chlorophenyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(S)-4-(2-fluorophenyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(S)-4-(azetidine-1-carbonyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(S)-N-hydroxy-4-(3-methoxyazetidine-1-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(3S)-N-hydroxy-4-(3-methoxypyrrolidine-1-carbonyl)-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(S)-N8-hydroxy-3-methyl-N4-(pyridin-3-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide+++(S)-N4-cyclohexyl-N8-hydroxy-3-methyl-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide+++(S)-N8-hydroxy-3-methyl-N4-(pyridin-2-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide+++(S)-N8-hydroxy-3-methyl-N4-(tetrahydro-2H-pyran-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide+++(S)-N8-hydroxy-N4,3-dimethyl-N4-(tetrahydro-2H-pyran-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide+++(S)-N8-hydroxy-3-methyl-N4-(pyridin-4-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4,8(5H)-dicarboxamide+++(S)-4-((1R,5R)-8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(S)-4-((1S,5S)-8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++(S)-4-(3,4-dihydro-2H-benzo[b][1,4]oxazine-4-carbonyl)-N-hydroxy-3-methyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++N-hydroxy-2-oxo-4-(piperidine-1-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepine-7-carboxamide++(S)-3-benzyl-N-hydroxy-4-(morpholine-4-carbonyl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine-8-carboxamide+++

EQUIVALENTS

While the present disclosure has been described in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand other variations thereof will be apparent to those of ordinary skillin the art. All such alternatives, modifications and variations areintended to fall within the spirit and scope of the present disclosure.

The invention claimed is:
 1. A compound of Formula I:

or a pharmaceutically acceptable salt, thereof, wherein: X¹ is O; X² andX⁴ are each CR¹R²; X³ is CR^(1′)R^(2′); Y¹ and Y⁴ are not bonded to—C(O)NHOH and are each independently N or CR¹; Y² and Y³ are eachindependently N or CR¹ when not bonded to —C(O)NHOH and Y² and Y³ are Cwhen bonded to —C(O)NHOH; wherein two of Y¹, Y², Y³, and Y⁴ are N; L isselected from a group consisting of a bond, —(CR¹R²)_(n)—, —C(O)O—,—C(O)NR³—, —S(O)₂—, —S(O)₂NR³—, —S(O)—, and —S(O)NR³—, wherein L isbound to the ring nitrogen through the carbonyl or sulfonyl group; R isindependently selected from the group consisting of —H, —C₁-C₆ alkyl,—C₂-C₆ alkenyl, —C₄-C₈ cycloalkenyl, —C₂-C₆ alkynyl, —C₃-C₈ cycloalkyl,—C₅-C₁₂ spirocycle, heterocyclyl, spiroheterocyclyl, aryl, andheteroaryl containing 1-5 heteroatoms selected from the group consistingof N, S, P, and O, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl,cycloalkyl, spirocyclyl, heterocyclyl, spiroheterocyclyl, aryl, orheteroaryl is optionally substituted with one or more substituentsselected from the group consisting of —OH, halogen, oxo, —NO₂, —CN, —R¹,—R², —OR³, —NHR³, —NR³R⁴, —S(O)₂NR³R⁴, —S(O)₂R¹, —C(O)R¹, —CO₂R¹,—NR³S(O)₂R¹, —S(O)R¹, —S(O)NR³R⁴, —NR³S(O)R¹, heterocyclyl, aryl, andheteroaryl containing 1-5 heteroatoms selected from the group consistingof N, S, P, and O; each R¹ and R² are independently, and at eachoccurrence, selected from the group consisting of —H, —R³, —R⁴, —C₁-C₆alkyl, —C₂-C₆ alkenyl, —C₄-C₈ cycloalkenyl, —C₂-C₆ alkynyl, —C₃-C₈cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5 heteroatomsselected from the group consisting of N, S, P, and O, —OH, halogen,—NO₂, —CN, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂,—N(C₁-C₆ alkyl)S(O)₂R⁵, —S(O)₂(C₁-C₆ alkyl), —(C₁-C₆ alkyl)S(O)₂R⁵,—C(O)C₁-C₆ alkyl, —CO₂C₁-C₆ alkyl, —N(C₁-C₆ alkyl)S(O)₂C₁-C₆ alkyl, and—(CHR⁵)_(n)NR³R⁴, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more substituents selected from the group consisting of —OH,halogen, —NO₂, oxo, —CN, —R⁵, —OR³, —NHR³, —NR³R⁴, —S(O)₂N(R³)₂,—S(O)₂R⁵, —C(O)R⁵, —CO₂R⁵, —NR³S(O)₂R⁵, —S(O)R⁵, —S(O)NR³R⁴, —NR³S(O)R⁵,heterocyclyl, aryl, and heteroaryl containing 1-5 heteroatoms selectedfrom the group consisting of N, S, P, and O; R^(1′) and R^(2′) areindependently, and at each occurrence, selected from the groupconsisting of —H, —C₁-C₆ alkyl, —C₂-C₆ alkenyl, —C₄-C₈ cycloalkenyl,—C₂-C₆ alkynyl, —C₃-C₈ cycloalkyl, heterocyclyl, —OH, halogen, —NO₂,—CN, —NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)₂R⁵, —S(O)₂(C₁-C₆ alkyl), —(C₁-C₆ alkyl)S(O)₂R⁵, —C(O)C₁-C₆alkyl, —CO₂C₁-C₆ alkyl, —N(C₁-C₆ alkyl)S(O)₂C₁-C₆ alkyl, and—(CHR⁵)_(n)NR³R⁴, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl,cycloalkyl, or heterocyclyl is optionally substituted with one or moresubstituents selected from the group consisting of —OH, halogen, —NO₂,oxo, —CN, —R⁵, —OR³, —NHR³, —NR³R⁴, —S(O)₂N(R³)₂, —S(O)₂R⁵, —C(O)R⁵,—CO₂R⁵, —NR³S(O)₂R⁵, —S(O)R⁵, —S(O)NR³R⁴, —NR³S(O)R⁵, heterocyclyl,aryl, and heteroaryl containing 1-5 heteroatoms selected from the groupconsisting of N, S, P, and O; R³ and R⁴ are independently, at eachoccurrence, selected from the group consisting of —H, —C₁-C₆ alkyl,—C₂-C₆ alkenyl, —C₄-C₈ cycloalkenyl, —C₂-C₆ alkynyl, —C₃-C₈ cycloalkyl,heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected fromthe group consisting of N, S, P, and O, —S(O)₂N(C₁-C₆ alkyl)₂,—S(O)₂(C₁-C₆ alkyl), —(C₁-C₆ alkyl)S(O)₂R⁵, —C(O)C₁-C₆ alkyl, —CO₂C₁-C₆alkyl, or —(CHR⁵)_(n)N(C₁-C₆ alkyl)₂, wherein each alkyl, alkenyl,cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl isoptionally substituted with one or more substituents selected from thegroup consisting of —OH, halogen, —NO₂, oxo, —CN, —R⁵, —O(C₁-C₆ alkyl),—NH(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —S(O)₂N(C₁-C₆ alkyl)₂,—S(O)₂NH(C₁-C₆ alkyl), —C(O)C₁-C₆ alkyl, —CO₂C₁-C₆ alkyl, —N(C₁-C₆alkyl)S(O)₂C₁-C₆ alkyl, —S(O)R⁵, —S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)R⁵, heterocyclyl, aryl, and heteroaryl containing 1-5heteroatoms selected from the group consisting of N, S, P, and O; or R³and R can combine with the nitrogen atom to which they are attached toform a heterocycle, wherein each heterocycle is optionally substitutedby —R¹, —R², —R⁴, —OR⁴, or —NR⁴R⁵; R⁵ is independently, and at eachoccurrence, selected from the group consisting of —H, —C₁-C₆ alkyl,—C₂-C₆ alkenyl, —C₄-C₈ cycloalkenyl, —C₂-C₆ alkynyl, —C₃-C₈ cycloalkyl,heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected fromthe group consisting of N, S, P, and O, —OH, halogen, —NO₂, —CN,—NHC₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂, —S(O)₂NH(C₁-C₆ alkyl), —S(O)₂N(C₁-C₆alkyl)₂, —S(O)₂C₁-C₆ alkyl, —C(O)C₁-C₆ alkyl, —CO₂C₁-C₆ alkyl, —N(C₁-C₆alkyl)SO₂C₁-C₆ alkyl, —S(O)(C₁-C₆ alkyl), —S(O)N(C₁-C₆ alkyl)₂, —N(C₁-C₆alkyl)S(O)(C₁-C₆ alkyl), and —(CH₂)_(n)N(C₁-C₆ alkyl)₂; and n isindependently, and at each occurrence, an integer from 0 to
 6. 2. Thecompound of claim 1, wherein the compound is of the Formula IA:

or a pharmaceutically acceptable salt thereof.
 3. The compound of claim2, wherein the compound is of the Formula IA-5:

or a pharmaceutically acceptable salt thereof.
 4. The compound of claim2, wherein the compound is of the Formula IA-6:

or a pharmaceutically acceptable salt thereof.
 5. The compound of claim2, wherein the compound is of the Formula IA-7:

or a pharmaceutically acceptable salt thereof.
 6. The compound of claim1, wherein the compound is of the Formula IB

or a pharmaceutically acceptable salt thereof.
 7. The compound of claim1, wherein L is —C(O)NR³—.
 8. The compound of claim 7, wherein at leastone of R^(1′) and R^(2′) is —H.
 9. The compound of claim 8, wherein oneof R^(1′) and R^(2′) is —C₁-C₆ alkyl.
 10. The compound of claim 9,wherein R³ and R combine with the nitrogen atom to which they areattached to form an optionally substituted heterocycle.
 11. The compoundof claim 9, wherein R is an optionally substituted group selected fromthe group consisting of —C₁-C₆ alkyl, —C₃-C₈ cycloalkyl, heterocyclyl,aryl, and heteroaryl.
 12. The compound of claim 1, wherein L is—(CR¹R²)_(n)—, —C(O)O—, or —S(O)₂—.
 13. The compound of claim 12,wherein at least one of R^(1′) and R^(2′) is —H.
 14. The compound ofclaim 13, wherein one of R^(1′) and R^(2′) is —C₁-C₆ alkyl.
 15. Thecompound of claim 12, wherein R is an optionally substituted groupselected from the group consisting of —C₁-C₆ alkyl, —C₃-C₈ cycloalkyl,heterocyclyl, aryl, and heteroaryl.
 16. The compound of claim 1, whereinL is a bond.
 17. The compound of claim 16, wherein at least one ofR^(1′) and R^(2′) is —H.
 18. The compound of claim 17, wherein one ofR^(1′) and R^(2′) is —C₁-C₆ alkyl.
 19. The compound of claim 16, whereinR is an optionally substituted group selected from the group consistingof —C₁-C₆ alkyl, —C₃-C₈ cycloalkyl, heterocyclyl, aryl, and heteroaryl,and wherein R is optionally substituted with a group selected from aryl,heteroaryl, and —C₃-C₈ cycloalkyl.
 20. A pharmaceutical compositioncomprising a compound of claim 1, and a pharmaceutically acceptablecarrier.